U.S. patent number 11,360,107 [Application Number 14/631,830] was granted by the patent office on 2022-06-14 for systems and methods for sample handling.
This patent grant is currently assigned to Labrador Diagnostics LLC. The grantee listed for this patent is Labrador Diagnostics LLC. Invention is credited to Samartha Anekal, Elizabeth A. Holmes, Chinmay Pangarkar, Timothy Smith, James R. Wasson, Daniel Young.
United States Patent |
11,360,107 |
Young , et al. |
June 14, 2022 |
Systems and methods for sample handling
Abstract
Systems and methods are provided for sample processing. A device
may be provided, capable of receiving the sample, and performing
one or more of a sample preparation, sample assay, and detection
step. The device may be capable of performing multiple assays. The
device may comprise one or more modules that may be capable of
performing one or more of a sample preparation, sample assay, and
detection step. The device may be capable of performing the steps
using a small volume of sample.
Inventors: |
Young; Daniel (Palo Alto,
CA), Anekal; Samartha (Palo Alto, CA), Holmes; Elizabeth
A. (Palo Alto, CA), Smith; Timothy (San Ramon, CA),
Pangarkar; Chinmay (Fremont, CA), Wasson; James R. (Los
Altos, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Labrador Diagnostics LLC |
Healdsburg |
CA |
US |
|
|
Assignee: |
Labrador Diagnostics LLC
(Wilmington, DE)
|
Family
ID: |
1000001202912 |
Appl.
No.: |
14/631,830 |
Filed: |
February 25, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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61944567 |
Feb 25, 2014 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N
35/1016 (20130101); G01N 35/00584 (20130101); G01N
35/10 (20130101); C12Q 3/00 (20130101); G01N
2035/00237 (20130101) |
Current International
Class: |
G01N
35/00 (20060101); G01N 35/10 (20060101); C12Q
3/00 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Office Action dated Jul. 8, 2015 for U.S. Appl. No. 14/490,653.
cited by applicant .
Office Action dated Jul. 8, 2015 for U.S. Appl. No. 14/490,658.
cited by applicant .
Office Action dated Mar. 24, 2016 for U.S. Appl. No. 14/490,653.
cited by applicant .
Office Action dated Apr. 14, 2016 for U.S. Appl. No. 14/490,658.
cited by applicant .
Office Action dated Sep. 23, 2016 for U.S. Appl. No. 14/490,653.
cited by applicant .
Office Action dated Jun. 5, 2017 for U.S. Appl. No. 14/490,653.
cited by applicant .
Notice of Allowance dated Oct. 26, 2016 for U.S. Appl. No.
14/490,658. cited by applicant .
Office Action dated Nov. 2, 2018 for U.S. Appl. No. 14/490,653.
cited by applicant .
Office Action dated Dec. 29, 2017 for U.S. Appl. No. 15/584,374.
cited by applicant .
Office Action dated May 24, 2019 for U.S. Appl. No. 14/490,653.
cited by applicant.
|
Primary Examiner: Chin; Christopher L
Assistant Examiner: Al-Ameen; Mohammad Ali
Claims
What is claimed is:
1. A method of performing at least 3 different assays selected from
immunoassays, cytometric assays, and general chemistry assays on a
biological sample, the method comprising: a) introducing the
biological sample having a volume of no greater than 500
microliters into a sample processing device, wherein the device
comprises: i) a sample handling system; ii) a detection station;
iii) a cytometry station comprising an imaging device and a stage
for receiving a microscopy cuvette; and iv) an assay station
comprising at least a first, a second, a third, and a fourth
independently movable assay unit; b) with the aid of the sample
handling system, transferring a portion of the biological sample to
each of the first, second, third, and fourth assay units, wherein a
different assay is performed in each of the first, second, third,
and fourth assay units; c) with the aid of the sample handling
system, transferring the first, second, third, and fourth assay
units to the detection station or cytometry station, wherein assay
units comprising immunoassays or general chemistry assays are
transferred to the detection station and assay units comprising
cytometric assays are transferred to the cytometry station; d) with
the aid of the detection station or cytometry station, obtaining
data measurements of the assay performed in each of the first,
second, third, and fourth assay units; and e) using a controller
operatively coupled to the sample handling system to instruct the
sample handling system to perform a test order that is not
pre-determined and is modified based on one or more detected
conditions, further comprising using a plurality of sensors to
monitor progress of sample processing and maintain or alter the
test order or schedule wherein if the system detects that
processing is taking longer than the predetermined amount of time
set forth in the schedule, the system speeds up processing or
adjusts any parallel processes; wherein the controller controls
reflex testing, wherein a first assay is a primary test, and a
second assay is a reflexed test, wherein if the result of first
assay meets a predefined criteria initiating the reflex test, then
the second assay is run with the same sample, wherein if a reflex
test order is detected, at least some of the steps of second assay
are performed before results for first assay are complete.
2. The method of claim 1 further comprising inserting a cartridge
into the sample processing device to locate the cartridge at a
cartridge receiving location.
3. The method of claim 2 further comprising inserting a vessel on
to the cartridge, wherein the vessel contain the sample.
4. The method of claim 3 wherein the cartridge comprises a vessel
having the biological sample and at least two types of pipette
tips.
5. The method of claim 1 wherein the sample processing device
further comprises a touchscreen display.
6. The method of claim 1 wherein the sample handling system
comprises a liquid handling system.
7. The method of claim 1 wherein the sample processing device
further comprises a centrifuge.
8. The method of claim 1 wherein the sample processing device
further comprises a magnet tool.
9. The method of claim 1 wherein the sample processing device
further comprises a spectrophotometer.
10. The method of claim 1 wherein the detection station comprises a
light source and an optical sensor.
11. The method of claim 1, wherein an assay station configured to
support i) the biological sample, ii) at least the first, the
second, and the third assay units, wherein the assay units are
fluidically isolated, and iii) reagents to perform A) at least one
luminescence assay; B) at least one absorbance, turbimetric, or
colorimetric assay; and C) at least one cytometry assay.
12. The method of claim 1, wherein the controller is operatively
coupled to the sample handling system, wherein the sample handling
system is instructed by the controller to i) transfer at least a
portion of the biological sample to first, second, and third assay
units; ii) transfer the first assay unit containing biological
sample to a detection station; iii) transfer the second assay unit
containing biological sample to a second detection station; and iv)
transfer the third assay unit containing biological sample to the
cytometry station.
13. The method of claim 1, wherein the biological sample has a
volume of 200 microliters or less.
14. A method of performing at least 3 different assays selected
from immunoassays, cytometric assays, and general chemistry assays
on a biological sample, the method comprising: a) introducing the
biological sample having a volume of no greater than 500
microliters into a sample processing device, wherein the device
comprises: i) a sample handling system; ii) a detection station;
iii) a cytometry station comprising an imaging device and a stage
for receiving a microscopy cuvette; and iv) an assay station
comprising at least a first, a second, a third, and a fourth
independently movable assay unit; b) with the aid of the sample
handling system, transferring a portion of the biological sample to
each of the first, second, third, and fourth assay units, wherein a
different assay is performed in each of the first, second, third,
and fourth assay units; c) with the aid of the sample handling
system, transferring the first, second, third, and fourth assay
units to the detection station or cytometry station, wherein assay
units comprising immunoassays or general chemistry assays are
transferred to the detection station and assay units comprising
cytometric assays are transferred to the cytometry station; d) with
the aid of the detection station or cytometry station, obtaining
data measurements of the assay performed in each of the first,
second, third, and fourth assay units; and e) using a controller
operatively coupled to the sample handling system to instruct the
sample handling system to perform a test order that is not
pre-determined and is modified based on one or more detected
conditions, further comprising using a plurality of sensors to
monitor progress of sample processing and maintain or alter the
test order or schedule wherein if the system detects that
processing is taking longer than the predetermined amount of time
set forth in the schedule, the system speeds up processing or
adjusts any parallel processes; wherein the controller controls
reflex testing, wherein a first assay is a primary test, and a
second assay is a reflexed test, wherein if the result of first
assay meets a predefined criteria initiating the reflex test, then
the second assay is run with the same sample, wherein if a reflex
test order is detected, at least some of the steps of second assay
are performed before results for first assay are complete; wherein
all reagents for use in testing is provided by a cartridge and
wherein the cartridge is pre-loaded with reagents for first assay
and second assay for reflex testing.
15. A method of performing at least 3 different assays selected
from immunoassays, cytometric assays, and general chemistry assays
on a biological sample, the method comprising: a) introducing the
biological sample having a volume of no greater than 500
microliters into a sample processing device, wherein the device
comprises: i) a sample handling system; ii) a detection station;
iii) a cytometry station comprising an imaging device and a stage
for receiving a microscopy cuvette; and iv) an assay station
comprising at least a first, a second, a third, and a fourth
independently movable assay unit; b) with the aid of the sample
handling system, transferring a portion of the biological sample to
each of the first, second, third, and fourth assay units, wherein a
different assay is performed in each of the first, second, third,
and fourth assay units; c) with the aid of the sample handling
system, transferring the first, second, third, and fourth assay
units to the detection station or cytometry station, wherein assay
units comprising immunoassays or general chemistry assays are
transferred to the detection station and assay units comprising
cytometric assays are transferred to the cytometry station; d) with
the aid of the detection station or cytometry station, obtaining
data measurements of the assay performed in each of the first,
second, third, and fourth assay units; and e) using a controller
operatively coupled to the sample handling system to instruct the
sample handling system to perform a test order that is not
pre-determined and is modified based on one or more detected
conditions, further comprising using a plurality of sensors to
monitor progress of sample processing and maintain or alter the
test order or schedule wherein if the system detects that
processing is taking longer than the predetermined amount of time
set forth in the schedule, the system speeds up processing or
adjusts any parallel processes; wherein the controller controls
reflex testing, wherein a first assay is a primary test, and a
second assay is a reflexed test, wherein if the result of first
assay meets a predefined criteria initiating the reflex test, then
the second assay is run with the same sample, wherein if a reflex
test order is detected, at least some of the steps of second assay
are performed before results for first assay are complete; wherein
a sequence in which assays are performed is altered based on
initial parameters, before assays are performed, based on one or
more detected conditions, one or more additional processes to run,
one or more processes to no longer run, one or more processes to
modify, one or more resource/component utilization modifications,
one or more detected error or alert condition, or one or more
unavailability of a resource and/or component.
Description
BACKGROUND OF THE INVENTION
The majority of clinical decisions are based on laboratory and
health test data, yet the methods and infrastructure for collecting
such data severely limit the quality and utility of the data
itself. Almost all errors in laboratory testing are associated with
human or pre-analytic processing errors, and the testing process
can take days to weeks to complete. Often times by the time a
practicing physician gets the data to effectively treat a patient
or determine the most appropriate intervention, he or she has
generally already been forced to treat a patient empirically or
prophylactically as the data was not available at the time of the
visit or patient triage. Earlier access to higher quality testing
information at the time of patient triage enables earlier
interventions and better management of disease progression to
improve outcomes and lower the cost of care.
Existing systems and methods for clinical testing suffer major
drawbacks from the perspectives of patients, medical care
professionals, taxpayers, and insurance companies. Today, consumers
can undergo certain specialized tests at clinics or other
specialized locations. If a test is to be conducted and the result
of which is to be eventually relied on by a doctor, physical
samples are transported to a location which performs the test on
the samples. For example, these samples may comprise blood from a
venous draw and are typically collected from a subject at the
specialized locations. Accessibility of these locations and the
venipuncture process in and of itself is a major barrier in
compliance and frequency of testing. Availability for visiting a
blood collection site, the fear of needles--especially in children
and elderly persons who, for example, often have rolling veins, and
the difficulty associated with drawing large amounts of blood
drives people away from getting tested even when it is needed.
Thus, the conventional sampling and testing approach is cumbersome
and requires a significant amount of time to provide test results.
Such methods are not only hampered by scheduling difficulties
and/or limited accessibility to collection sites for subjects to
provide physical samples but also by the batch processing of
samples in centralized laboratories and the associated turn around
time in running laboratory tests. As a result, the overall turn
around time involved in getting to the collection site, acquiring
the sample, transporting the sample, testing the sample and
reporting and delivering results becomes prohibitive and severely
limits the timely provision of the most informed care from a
medical professional. This often results in treatment of symptoms
as opposed to underlying disease conditions or mechanisms of
disease progression.
In addition, traditional techniques are problematic for certain
diagnoses. Some tests may be critically time sensitive, but take
days or weeks to complete. Over such a time, a disease can progress
past the point of treatment. In some instances, follow-up tests are
required after initial results, which take additional time as the
patient has to return to the specialized locations. This impairs a
medical professional's ability to provide effective care.
Furthermore, conducting tests at only limited locations and/or
infrequently reduces the likelihood that a patient's status can be
regularly monitored or that the patient will be able to provide the
samples quickly or as frequently as needed. For certain diagnoses
or conditions, these deficiencies inevitably cause inadequate
medical responses to changing and deteriorating physiological
conditions. Traditional systems and methods also affect the
integrity and quality of a clinical test due to degradation of a
sample that often occurs while transporting such sample from the
site of collection to the place where analysis of the sample is
performed. For example, analytes decay at a certain rate, and the
time delay for analysis can result in loss of sample integrity.
Different laboratories also work with different quality standards
which can result in varying degrees of error. Additionally,
preparation and analysis of samples by hand permits upfront human
error to occur at various sample collection sites and laboratories.
These and other drawbacks inherent in the conventional setup make
it difficult to perform longitudinal analyses, especially for
chronic disease management, with high quality and reliability
Furthermore, such conventional analytical techniques are often not
cost effective. Excessive time lags in obtaining test results lead
to delays in diagnoses and treatments that can have a deleterious
effect on a patient's health; as a disease progresses further, the
patient then needs additional treatment and too often ends up
unexpectedly seeing some form of hospitalization. Payers, such as
health insurance companies and taxpayers contributing to
governmental health programs, end up paying more to treat problems
that could have been averted with more accessible and faster
clinical test results.
SUMMARY OF THE INVENTION
Being able to detect a disease or the onset of a disease in time to
manage and treat it is a capability deeply sought after by patients
and providers alike but one that has yet to be realized in the
current healthcare system where detection too often coincides with
fatal prognoses.
In some embodiments, a fluid handling system includes a fluid
uptake and/or retention system. In some cases, a fluid handling
system includes a pipette. In some embodiments, the fluid handling
system is attached to each individual module among a plurality of
modules of a system described above, alone or in combination with
other systems. In some embodiments, a system above, alone or in
combination, includes a housing that comprises a rack for
supporting the plurality of modules. The housing can be dimensioned
to be no more than 3 m.sup.3, or no more than 2 m.sup.3.
In some embodiments, a system above, alone or in combination,
comprises a control system having programmable commands for
performing a point-of-service service at a designated location.
In some embodiments, a system above, alone or in combination,
includes a fluid handling system. In some cases, the fluid handling
system includes a pipette selected from the group consisting of a
positive displacement pipette, air displacement pipette and
suction-type pipette.
In some embodiments, a system above, alone or in combination,
includes a plurality of modules. In some cases, an individual
module comprises fluid handling tips configured to perform one or
more of procedures selected from the group consisting of
centrifugation, sample separation, immunoassay, nucleic acid assay,
receptor-based assay, cytometric assay, colorimetric assay,
enzymatic assay, electrophoretic assay, electrochemical assay,
spectroscopic assay, chromatographic assay, microscopic assay,
topographic assay, calorimetric assay, turbidimetric assay,
agglutination assay, radioisotope assay, viscometric assay,
coagulation assay, clotting time assay, protein synthesis assay,
histological assay, culture assay, osmolarity assay, and
combinations thereof. In some situations, the nucleic acid assay is
selected from the group consisting of nucleic acid amplification,
nucleic acid hybridization, and nucleic acid sequencing.
In some embodiments, a system above, alone or in combination,
includes a plurality of modules, and each individual module of said
plurality of modules comprises (a) a fluid handling system
configured to transfer a sample within said individual module or
from said individual module to another module within said system,
(b) a plurality of assay units configured to perform multiple types
of assays, and (c) a detector configured to detect signals
generated from said assays. In some situations, the multiple types
of assays are selected from the group consisting of immunoassay,
nucleic acid assay, receptor-based assay, cytometric assay,
colorimetric assay, enzymatic assay, electrophoretic assay,
electrochemical assay, spectroscopic assay, chromatographic assay,
microscopic assay, topographic assay, calorimetric assay,
turbidimetric assay, agglutination assay, radioisotope assay,
viscometric assay, coagulation assay, clotting time assay, protein
synthesis assay, histological assay, culture assay, osmolarity
assay, and combinations thereof.
In some embodiments, a system above, alone or in combination,
includes a plurality of modules, and each individual module
comprises a centrifuge.
In some embodiments, a system above, alone or in combination,
further comprises a module providing a subset of the sample
preparation procedures or assays performed by at least one module
of said system.
In some embodiments, a system above, alone or in combination,
comprises an assay station that includes a thermal block.
In some embodiments, a sample includes at least one material
selected from the group consisting of fluid sample, tissue sample,
environmental sample, chemical sample, biological sample,
biochemical sample, food sample, or drug sample. In some cases, the
sample includes blood or other bodily fluid, or tissue.
In some embodiments, a system above, alone or in combination, is
configured for two-way communication with a point of service
server. In some cases, the two-way communication is wireless.
In some embodiments, a system above, alone or in combination,
includes a plurality of modules, and each member of the plurality
of modules is swappable with another module.
In some embodiments, a system above, alone or in combination,
includes an assay station that comprises discrete assay units. In
some cases, the discrete assay units are fluidically isolated assay
units.
In some embodiments, a system above, alone or in combination, is
configured for longitudinal analysis at a coefficient of variation
less than or equal to 10%, or less than or equal to 5%, or less
than or equal to 3%.
In some embodiments, a system above, alone or in combination,
includes a fluid handling system that includes an optical
fiber.
In some embodiments, a system above, alone or in combination,
includes a fluid handling system that includes a pipette.
In some embodiments, a system above, alone or in combination,
comprises an image analyzer.
In some embodiments, a system above, alone in combination,
comprises at least one camera in a housing of the system. In some
cases, the at least one camera is a charge-coupled device (CCD)
camera. In some situations, the at least one camera is a lens-less
camera.
In some embodiments, a system above, alone or in combination,
comprises a controller that includes programmable commands for
performing a point-of-service service at a designated location.
In some embodiments, a system above, alone or in combination, is a
plug-and-play system configured to provide a point-of-service
service. In some cases, the point-of-service service is a point of
care service provided to a subject having a prescription from the
subject's caretaker, said prescription being prescribed for testing
the presence or concentration of an analyte from said subject's
biological sample.
In some embodiments, a system above, alone or in combination,
includes a plurality of modules, and each member of the plurality
of modules comprises a communication bus in communication with a
station configured to perform the at least one sample preparation
procedure or the at least one type of assay.
In some embodiments, a system above, alone or in combination,
includes a supporting structure. In some cases, the supporting
structure is a rack. In some situations, the rack does not include
a power or communication cable; in other situations, the rack
includes a power or communication cable. In some embodiments, the
supporting (or support) structure includes one or more mounting
stations. In some cases, the supporting structure includes a bus in
communication with a mounting station of said one or more mounting
stations.
In some embodiments, the bus is for providing power to individual
modules of the system. In some embodiments, the bus is for enabling
communication between a controller of the system (e.g.,
plug-and-play system) and individual modules of the system. In some
situations, the bus is for enabling communication between a
plurality of modules of the system, or for enabling communication
between a plurality of modules of a plurality of systems.
In some embodiments, a system, alone or in combination, includes a
plurality of modules, and each individual modules of the plurality
of modules is in wireless communication with a controller of the
system. In some cases, wireless communication is selected from the
group consisting of Bluetooth communication, radiofrequency (RF)
communication and wireless network communication.
In some embodiments, a method for processing a sample, alone or in
combination with other methods, comprises providing a system above,
alone or in combination. The system comprises multiple modules
configured to perform simultaneously (a) at least one sample
preparation procedure selected from the group consisting of sample
processing, centrifugation, magnetic separation and chemical
processing, and/or (b) at least one type of assay selected from the
group consisting of immunoassay, nucleic acid assay, receptor-based
assay, cytometric assay, colorimetric assay, enzymatic assay,
electrophoretic assay, electrochemical assay, spectroscopic assay,
chromatographic assay, microscopic assay, topographic assay,
calorimetric assay, turbidimetric assay, agglutination assay,
radioisotope assay, viscometric assay, coagulation assay, clotting
time assay, protein synthesis assay, histological assay, culture
assay, osmolarity assay, and combinations thereof within a module.
Next, the system (or a controller of the system) tests for the
unavailability of resources or the presence of a malfunction of (a)
the at least one sample preparation procedure or (b) the at least
one type of assay. Upon detection of the malfunction within at
least one module, the system uses another module within the system
or another system in communication with the system to perform the
at least one sample preparation procedure or the at least one type
of assay.
In some cases, the system processes the sample at a point of
service location.
In some cases, the system is in wireless communication with another
system.
In some cases, multiple modules of the system are in electrical,
electro-magnetic or optoelectronic communication with one
another.
In some cases, multiple modules of the system are in wireless
communication with one another.
An aspect of the invention includes a fluid handling apparatus
comprising: a plurality of pipette heads, wherein an individual
pipette head comprises a pipette nozzle configured to connect with
a tip that is removable from the pipette nozzle; a plurality of
plungers that are individually movable, wherein at least one
plunger is within a pipette head and is movable within the pipette
head; and a motor configured to effect independent movement of
individual plungers of the plurality.
Another aspect of the invention includes a fluid handling apparatus
comprising a plurality of pipette heads, wherein an individual
pipette head comprises a pipette nozzle configured to connect with
a tip that is removable from the pipette nozzle; a plurality of
plungers that are individually movable, wherein at least one
plunger is within a pipette head and is movable within the pipette
head; and an actuator configured to effect independent movement of
individual plungers of the plurality.
Another aspect of the invention includes a fluid handling apparatus
comprising a plurality of pipette heads, wherein an individual
pipette head comprises a pipette nozzle configured to connect with
a tip that is removable from said pipette nozzle, wherein the fluid
handling apparatus is capable of dispensing and/or aspirating 0.5
microliters ("uL") to 5 milliliters ("mL") of fluid while
functioning with a coefficient of variation of 5% or less.
A fluid handling apparatus may be provided in accordance with an
aspect of the invention, the apparatus comprising: at least one
pipette head, wherein an individual pipette head comprises a
pipette nozzle configured to connect with a tip that is removable
from said nozzle; at least one plunger within a pipette head of
said plurality, wherein the plunger is configured to be movable
within the pipette head; and at least one motor configured to
permit movement of the plurality of plunger that is not
substantially parallel to the removable tip.
Another aspect of the invention provides a fluid handling apparatus
comprising at least one pipette head, wherein an individual pipette
head comprises a pipette nozzle configured to connect with a tip
that is removable from said nozzle; at least one plunger within a
pipette head of said plurality, and wherein the plunger is
configured to be movable within the pipette head; and at least one
actuator configured to permit movement of the plurality of plungers
that are not substantially parallel to the removable tip.
Another aspect of the invention may provide a fluid handling
apparatus comprising: at least one pipette head, wherein an
individual pipette head comprises a pipette nozzle configured to
connect with a tip that is removable from said nozzle, wherein said
at least one pipette head has a fluid path of a given length that
terminates at the pipette nozzle, and wherein the length of the
fluid path is adjustable without affecting movement of fluid from
the tip when the tip and the pipette nozzle are engaged.
Another aspect of the invention provides a fluid handling apparatus
comprising at least one pipette head, wherein an individual pipette
head comprises a pipette nozzle configured to connect with a tip
that is removable from said nozzle, wherein said at least one
pipette head has a fluid path of a given length that terminates at
the pipette nozzle, and wherein the length of the fluid path is
adjustable without affecting movement of fluid from the tip when
the tip and the pipette nozzle are engaged.
Additionally, aspects of the invention may include a fluid handling
apparatus comprising: a removable tip; and at least one pipette
head, wherein an individual pipette head comprises a pipette nozzle
configured to connect with the tip that is removable from said
pipette nozzle, wherein the apparatus is operably connected to an
image capture device that is configured to capture an image within
and/or through the tip.
Other goals and advantages of the invention will be further
appreciated and understood when considered in conjunction with the
following description and accompanying drawings. While the
following description may contain specific details describing
particular embodiments of the invention, this should not be
construed as limitations to the scope of the invention but rather
as an exemplification of preferable embodiments. For each aspect of
the invention, many variations are possible as suggested herein
that are known to those of ordinary skill in the art. A variety of
changes and modifications can be made within the scope of the
invention without departing from the spirit thereof.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in
this specification are herein incorporated by reference to the same
extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are used, and the accompanying drawings of which:
FIG. 1 shows an example of a system comprising a sample processing
device and an external controller in accordance with an embodiment
of the invention.
FIG. 2 shows an example of a sample processing device.
FIG. 3 shows an example of a module having a sample preparation
station, assay station, detection station, and a fluid handling
system.
FIG. 4 provides an example of a rack supporting a plurality of
modules having a vertical arrangement.
FIG. 5 provides an example of a rack supporting a plurality of
modules having an array arrangement.
FIG. 6 illustrates a plurality of modules having an alternative
arrangement.
FIG. 7 shows an example of a sample processing device having a
plurality of modules.
FIG. 7A shows a non-limiting example of a sample processing device
having a plurality of modules.
FIG. 7B shows a non-limiting example of a sample processing device
having a plurality of modules.
FIG. 7C shows a non-limiting example of a sample processing device
having a plurality of modules.
FIG. 8 shows a plurality of racks supporting one or more
modules.
FIG. 9 shows an example of a module with one or more components
communicating with a controller.
FIG. 10 shows a system having a plurality of modules mounted in
bays (including, e.g., on the racks).
FIG. 11 shows a plurality of plots illustrating a parallel
processing routine.
FIG. 12 shows an example of a fluid handling apparatus in a
retracted position, provided in accordance with an embodiment of
the invention.
FIG. 12A shows a collapsed fluid handling apparatus as previously
described, in a fully retracted position.
FIG. 12B shows a retracted fluid handling apparatus, in a full
z-drop position.
FIG. 13 shows an example of a fluid handling apparatus in an
extended position in accordance with an embodiment of the
invention.
FIG. 14 shows a front view of a fluid handling apparatus.
FIG. 15 shows a side view of a fluid handling apparatus.
FIG. 16 shows another side view of a fluid handling apparatus.
FIG. 17 shows a rear perspective view of a fluid handling
apparatus.
FIG. 18 provides an example of a fluid handling apparatus used to
carry a sample processing component.
FIG. 19 shows a side view of a fluid handling apparatus useful for
carrying a sample processing component.
FIG. 20 shows a point of service device having a display, in
accordance with an embodiment of the invention. The display
includes a graphical user interface (GUI).
FIG. 21 provides an example of an expand/contract elastomer
deflection tip pick-up interface.
FIG. 22 provides an example of a vacuum gripper tip pick-up
interface.
FIG. 23 provides an example of a pipette module in accordance with
an embodiment of the invention.
FIG. 24A shows an example of modular pipette having a raised
shuttle in a full dispense position.
FIG. 24B shows an example of modular pipette having a lowered
shuttle in a full dispense position.
FIGS. 24C and 24D show non-limiting examples of pipette
configurations according to embodiments described herein.
FIG. 25A provides a top view of an example of a magnetic
control.
FIG. 25B provides a side view of the magnetic control.
FIG. 26 provides an example of a cuvette and cuvette carrier.
FIG. 27A shows an example of a carrier (e.g., cuvette), in
accordance with an embodiment of the invention.
FIG. 27B shows additional views of a carrier (e.g., cuvette).
FIG. 28 shows an example of a tip.
FIG. 29 an example of a vial strip.
FIG. 30 shows another example of a vial strip.
FIGS. 31A-31G show non-limiting examples of spectrophotometers
according to embodiments described herein.
FIGS. 32-33 show non-limiting examples of embodiments of cartridges
as described herein.
FIG. 34-35 show non-limiting examples of cartridge covers according
to embodiments described herein.
FIG. 36 shows non-limiting examples of absorbant pad assembly
according to embodiments described herein.
FIG. 37 shows a non-limiting example of sample processing tip
according to embodiments described herein.
FIGS. 38A and 38B show non-limiting examples of cartridges with
thermal conditioning element(s) according to embodiments described
herein.
FIGS. 39 to 40 show non-limiting examples of microfluidic
cartridges according to embodiments described herein.
FIG. 41 shows a non-limiting example of a cartridge according to
embodiments described herein.
FIGS. 42 to 45 show non-limiting examples of thermal conditioning
element(s) according to embodiments described herein.
FIGS. 46 to 50 show non-limiting examples of centrifuge vessel
imaging configurations according to embodiments described
herein.
FIG. 51 shows an example of a nucleic acid assay station.
FIG. 52 shows a schematic according to at least one embodiment
described herein.
DETAILED DESCRIPTION OF THE INVENTION
While various embodiments of the invention have been shown and
described herein, it will be obvious to those skilled in the art
that such embodiments are provided by way of example only. Numerous
variations, changes, and substitutions may occur to those skilled
in the art without departing from the invention. It should be
understood that various alternatives to the embodiments of the
invention described herein may be employed in practicing the
invention.
This document contains material subject to copyright protection.
The copyright owner (Applicant herein) has no objection to
facsimile reproduction of the patent documents and disclosures, as
they appear in the US Patent and Trademark Office patent file or
records, but otherwise reserves all copyright rights whatsoever.
The following notice shall apply: Copyright 2013-15 Theranos,
Inc.
FIG. 1 illustrates an example of a system. A system may comprise
one or more sample processing device 100 that may be configured to
receive a sample and/or to conduct multi-purpose analysis of one or
more sample(s) or types of samples sequentially or simultaneously.
Analysis may occur within the system. Analysis may or may not occur
on the device. A system may comprise one, two, three or more sample
processing devices. The sample processing devices may or may not be
in communication with one another or an external device. Analysis
may or may not occur on the external device. Analysis may be
affected with the aid of a software program and/or a health care
professional. In some instances, the external device may be a
controller 110.
Systems for multi-purpose analysis may comprise one or more groups
of sample processing devices. Groups of sample processing devices
may comprise one or more device 100. Devices may be grouped
according to geography, associated entities, facilities, rooms,
routers, hubs, care providers, or may have any other grouping.
Devices within groups may or may not be in communication with one
another. Devices within groups may or may not be in communication
with one or more external devices.
Sample processing devices may comprise one, two or more modules
130. Modules may be removably provided to the devices. Modules may
be capable of effecting a sample preparation step, assay step,
and/or detection step. In some embodiments, each module may be
capable of effecting a sample preparation step, assay step, and
detection step. In some embodiments, one or more modules may be
supported by a support structure 120, such as a rack. Zero, one,
two or more rack(s) may be provided for a device.
Modules may comprise one, two or more components 140 that may be
capable of effecting a sample preparation step, assay step, and/or
detection step. Module components may also include reagents and/or
vessels or containers that may enable a sample preparation step,
assay step, and/or detection step. Module components may assist
with the sample preparation step, the assay step, and/or detection
step. A device may comprise one or more component that is not
provided within a module. In some instances, a component may be
useful for only one of a sample preparation step, assay step,
and/or detection step. Examples of components are provided in
greater detail elsewhere herein. A component may have one or more
subcomponents.
In some instances, a hierarchy may be provided wherein a system
comprises one or more groups of devices, a group of devices
comprises one or more device, a device may optionally comprise one
or more rack which may comprise one or more module, a device may
comprise one or more module, a module and/or device may comprise
one or more components, and/or a component may comprise one or more
subcomponents of the component. One or more level of the hierarchy
may be optional and need not be provided in the system.
Alternatively, all levels of hierarchy described herein may be
provided within the system. Any discussion herein applying to one
level of hierarchy may also apply to other levels of
hierarchies.
A sample processing device is provided in accordance with an aspect
of the invention. A sample processing device may comprise one or
more components. The sample processing device may be configured to
receive a sample and/or to conduct one or more sample preparation
step, assay step, and/or detection step. The sample preparation
step, assay step, and/or detection step may be automated without
requiring human intervention.
In some embodiments, a system provided herein may be configured as
follows: The system may contain a sample processing device and,
optionally an external device. The external device may be, for
example, a remote server or cloud-based computing infrastructure.
The sample processing device may contain a housing. Within the
housing of the device, there may be one or more modules. The
modules may be supported by a rack or other support structure. The
modules may contain one or more components or stations. Components
and stations of a module may include, for example, assay stations,
detection stations, sample preparation stations, nucleic acid assay
stations, cartridges, centrifuges, photodiodes, PMTs,
spectrophotometers, optical sensors (e.g. for luminescence,
fluorescence, absorbance, or colorimetry), cameras, sample handling
systems, fluid handling systems, pipettes, thermal control units,
controllers, and cytometers. Components and stations of a module
may be removable or insertable into the module. The components and
stations of a module may contain one or more sub-components or
other items which may be part of or may be supported by a component
or station. Sub-components may include, for example, assay units,
reagent units, tips, vessels, magnets, filters, and heaters.
Sub-components of a components or station may be removable or
insertable into the component or station. In addition, the device
may contain one or more additional components which may be part of
a module, or which may be elsewhere in the device (e.g. on the
housing, rack, or between modules) such as a controller,
communication unit, power unit, display, sample handing system,
fluid handling system, processor, memory, robot, sample
manipulation device, detection unit. The system or device may have
one or more cartridges. The cartridges may be insertable or
removable from the device. The cartridges may contain, for example
reagents for performing assays or biological samples. The device
may have one or more controllers, including one or both of
device-level and module-level controllers (e.g. where the device
level controller is configured to direct certain procedures to be
performed on certain modules and where the module level controller
is configured to direct the components or stations to execute
particular steps for sample preparation, sample assaying, or sample
detection. In an alternative, a device-level controller may be
connected to modules and components of the module, to perform both
of these functions). The device may have one or more sample
handling system, including both device-level and module-level
sample handling system (e.g. where the device level sample handling
system is configured to move samples or components between modules
and where the module level sample handling system is configured to
move samples or components within a module. In an alternative, a
device level sample handling system may be configured to perform
both of these functions). The sample processing device may be in
two-way communication with the external device, such that the
sample processing device is configured to send information to the
external device, and also to receive information from the external
device. The external device may, for example, send protocols to the
sample processing device.
In some embodiments, a device may be or comprise a cartridge. The
cartridge may be removable from a large device. Alternatively, the
cartridge may be permanently affixed to or integral to the device.
The device and/or the cartridge may (both) be components of a
disposable such as a patch or pill. In some embodiments, an assay
station may comprise a cartridge.
A cartridge may be a universal cartridge that can be configured for
the same selection of tests. Universal cartridges may be
dynamically programmed for certain tests through remote or on-board
protocols. In some cases, a cartridge can have all reagents on
board and optionally server-side (or local) control through two-way
communication systems. In such a case, a system using such a
disposable cartridge with substantially all assay reagents on board
the cartridge may not require tubing, replaceable liquid tanks, or
other aspects that demand manual maintenance, calibration, and
compromise quality due to manual intervention and processing steps.
Use of a cartridge provided herein containing all reagents within
the cartridge necessary for performing one or more assays with a
system or device provided herein may permit the device or system to
not have any assay reagents or disposables stored within the
device.
Referring now to FIG. 32, one embodiment of a cartridge 9900 will
now be described. This embodiment shows that there may be a
plurality of different regions 9920 to 9940 on the cartridge 9900
to provide different types of devices, tips, reagents, reaction
locations, or the like. The mix of these elements depends on the
types of assays to be performed using the cartridge 9900. By way of
nonlimiting example, the cartridge 9900 may have regions to
accommodate one or more sample containers, pipette tips, microscopy
cuvette, large volume pipette tip, large volume reagent well, large
volume strip, cuvette with a linear array of reaction vessel, round
vessels, cap-removal tip, centrifuge vessel, centrifuge vessel
configured for optical measurement(s), nucleic acid amplification
vessels. Any one of the foregoing may be in the different regions
9920 to 9940. Some may arrange the tips and vessels in arrays
similar to those of the cartridges shown in commonly assigned U.S.
Pat. No. 8,088,593, fully incorporated herein by reference for all
purposes.
By way of non-limiting example, the reagents may also vary in the
cartridge and may be selected to include at least those desired to
perform at least two or more types of assay panels such as but not
limited to the lipid panel and a chem14 panel or other combination
of two or more different laboratory testing panels. For example,
some cartridges may have reagents, diluents, and/or reaction
vessels to support at least two different assay types from nucleic
acid amplification, general chemistry, immunoassay, or
cytometry.
Any one or more of the components of the cartridge may be
accessible by a sample handling system of the system. The different
zones in the cartridge may be configured to match the pitch of the
pipette heads used in the system. Optionally, some zones are
configured to be at pitches that are multiples of or fractions of
the pitch of the pipette heads. For example, some components of the
cartridge are at 1/3.times. of the pitch, others at 1/2.times. of
the pipette pitch, others at a 1.times. pitch, others at a 2.times.
pitch, while still others at a 4.times. pitch.
Referring still to FIG. 32, it should be understood that there may
be components located at one plane of the cartridge while other are
located at lower or higher planes. For example, some components may
be located below a cuvette or other component. Thus, once the upper
component is removed, the lower components become accessible. This
multi-layer approach provides for greater packing density in terms
of components on a cartridge. There may also be locating features
on the cartridge 9900 such as but not limited to rail 9834 that is
configured to engage matching slot on the cartridge receiving
location in the system. The cartridge may also have registration
features (physical, optical, or the like) that allow the system to
accurately engage components of the cartridge once the cartridge is
recognized by the system. By way of non-limiting example, although
components may be removed from the cartridge 9900 during assay
processing, it is understood that some embodiments may permit the
return of all components back to the cartridge for unified
disposal. Optionally, in some embodiments of the system may have
disposal areas, containers, chutes, or the like to discard those
components of the cartridge not returned to the cartridge prior to
ejecting the cartridge from the system. In some embodiments, these
areas may be dedicated areas of the system for receiving waste.
Referring now to FIG. 33, another embodiment of cartridge 9901 will
now be described. This one uses a reduced height cartridge 9901
wherein the sidewalls have a reduced vertical height. The provides
for less material use for the disposable and brings the reaction
vessels and/or reagents.
Referring now to FIG. 34, yet another feature of at least some
cartridges will now be described. FIG. 34 shows a side view of a
cartridge 9900 with a lid 9970, wherein the lid 9970 is removable
upon insertion of the cartridge 9900 into the system and will
re-engage the cover when the cartridge 9900 is removed from the
system. Such features may be advantageous for increasing the
security and protection of the components of the cartridge (e.g. to
prevent tampering or inadvertent introduction of external matter).
As seen in FIG. 34, there is an engagement feature 9972 such as but
not limited to snap that engages a locking feature 9974 in the body
of the cartridge 9900. A release mechanism 9976 such as but not
limited to a pin can be inserted into an opening where it can
contact the locking feature 9974 and move it to a release position.
This allows one end of the lid 9970 to be disengaged automatically
when the cartridge 9900 is inserted into system. Optionally, the
release mechanism 9976 may have pins that actuate so that the
release of the lid 9970 is based on when the system actuates to
unlock the locking feature 9974. In one non-limiting example, a
spring mechanism 9980 such as but not limited to a torsional spring
can automatically lift open the lid 9970 as indicated by arrow 9982
after the locking mechanism 9974 is disengaged. When ejecting the
cartridge 9900, the motion of the cartridge 9900 out of the device
will cause the lid 9970 in the open position to engage a
horizontally or otherwise mounted closure device 9984 (shown in
phantom) that will move the lid 9970 to a closed position due the
motion of the cartridge 9900 as indicated by arrow 9986 as it
passes under the device 9984. In the present embodiment, the spring
mechanism 9980 is engaged to the cartridge 9900 through openings
9978 (see FIG. 32).
FIG. 35 shows a perspective view of one embodiment of the lid 9970
that engages over a cartridge 9900. This lid may be configured to
retain all of the various components of the cartridge 9900 inside
the cartridge when the cartridge is not in the system. The use of
dual engagement features 9972 more securely holds the lid 9970 to
the cartridge and makes it more difficult for a user to
accidentally open the lid 9970 as it uses two or more points of
engagement with the locking mechanism of the cartridge. As seen in
FIG. AC, there is also a cut-out portion 9988 that allow for the
sample containers to be placed into the cartridge 9900 before the
cartridge 9900 is loaded into the system. In one non-limiting
example, this can simplify use of the cartridge as this is only
allows the sample container(s) to be placed in one location in the
cartridge 9900, thus making the user interaction with the cartridge
for loading sample much less variable or subject to error. The lid
9970 can also be opaque to prevent the user from being distracted
by vessels and elements in the cartridge, instead focusing the
user's attention to the only available open slot, which in the
current embodiment is reserved for the sample container(s) which
can only be inserted in a particular orientation due to the keyed
shape of the opening.
Referring now to FIG. 36, it should be understood that the
cartridge 9900 may also contain an absorbent pad assembly 10000
that is used to remove excess fluid from the various tips, vessels,
or other elements. In one embodiment, the absorbent pad assembly
10000 has a multi-layer configuration comprising a spacer 10002,
the absorbent pad 10004, and an adhesive layer 10006. Some
embodiments may or may not have the spacer layer 10002 which may be
made of material such as but not limited to acrylic or other
similar material. The shape of the openings in the spacer 10002 is
sized to allow for features such as but not limited to pipettes tip
to enter spacer layer 10002 to clean the tip for excess fluid
without contaminating the absorbent pad 10004 for adjacent
openings. Optionally, it should be understood that the absorbent
material 10004 may also be used alone or with adhesive or other
material to cover certain reagent or other zones such that a tip
would penetrate through the absorbent material 10004 in order to
reach the reagent below. This would provide for removal of excess
fluid on the outside of the tips on insertion and/or withdrawal of
the tip, and may aid in the reduction of cross-reactivity. In one
embodiment, this may be like a burst-able membrane of the absorbent
material. Some embodiments may use tips that are linear and not
conical in shape at the distal portion so that contact with the
absorbent material is not lost due to variation in tip diameter,
resulting in a less than thorough wiping of fluid from an outside
portion of the tip.
In some embodiments, tips may be configured such that they do not
retain excess fluid on the outside of the tip, and are not used
with an absorbent pad.
Referring now to FIG. 37, it should be understood that the
cartridge may also include various types of specialized tips or
elements for specific functions. By way of non-limiting example as
seen in FIG. 37, a sample preparation tip 10050 will now be
described. In this embodiment of a sample preparation tip, the
plunger 10052 of the tip 10050 interfaces with a single minitip
nozzle at opening 10054; the pipette nozzle can be set to "pull" to
produce a vacuum that allows the plunger to stay on the nozzle more
securely. In the present embodiment, the barrel part 10056 of the
sample preparation tip 10050 interfaces with two minitip nozzles of
the pipette at cavities 10058 and 10060. In this manner, the
pipette system uses multiple heads with nozzles thereon to both
move the hardware of the tip 10050 and to aspirate using the
plunger 10052.
In the present embodiment, the tip 10050 may include a resin
portion 10070 that may be bound above and below by frits 10072 and
10074. Frit material may be compatible with sample purification
chemistry and not leach any carryover inhibition into the
downstream assay. Optionally, frit material should not bind to the
biomolecule of interest, or must be chemically treated or surface
passivated to prevent such. Optionally, frit material may be porous
with an appropriate pore such that the resin remains within the
confines of its cavity. Optionally, frit must be sized such that
the interference fit between the barrel and the frit is enough to
hold it in place against typical operating fluid pressures. By way
of non-limiting example, the resin portion 10070 may be chosen such
that it binds optimally with the biomolecule of choice, which can
include but is not limited to bare and chemically modified versions
of silica, zirconia, polystyrene or magnetic beads.
In one embodiment, the method for using the tip 100050 may involve
the aspiration of lysed unpurified sample mixed with binding buffer
through the resin 10070. In such an example, DNA or biomolecule of
choice will bind to the resin 10070 in the appropriate salt
conditions and remaining fluid is dispensed into waste. The method
may involve aspiration of wash buffers to clean the bound sample
and dispense fluid into waste vessel. This may be repeated multiple
times as desired to obtain a clean sample. The method may further
include aspiration and dispense of heated air in order to dry to
resin to remove residual solvents and any carryover inhibition that
may interfere with the downstream assay. Optionally, the tip 10050
may be used for aspiration of elution buffer to remove the bound
molecule of interest, and may allow the elution buffer to
completely saturate the resin before dispensing into an appropriate
collection vessel.
In some embodiments, a pipette tip may contain a septa, such that
there is a seal between the sample intake portion of a pipette tip,
and the path of an actuation mechanism of the pipette (e.g. the
piston block).
In some embodiments, a pipette nozzle and pipette tip may have
threads, such that the pipette tip may be threaded onto the tip
(e.g. by rotation). The nozzle may rotate to thread the tip onto
the nozzle, or the tip may rotate. The tip may be "locked" in place
on the nozzle upon threading the tip onto the pipette nozzle. The
tip may be "unlocked" by rotating the nozzle or the tip in the
opposite direction as used for loading the tip onto the nozzle.
Referring now to FIG. 38, in some embodiments, the cartridge 9800
contains at least one thermal device 9802 such as a chemical
reaction pack for generating heat locally to enhance kinetics
and/or for heating a mixture. The chemical reaction pack may
contain chemicals such as sodium acetate or calcium chloride. This
may be particularly desirable in situations where the cartridge
9800, prior to use, is stored in a refrigerated condition such as
but not limited to the 0.degree. C. to 8.degree. C. range for days
to weeks. Optionally, the temperature range during cold storage may
be in the range of about -20.degree. C. to 8.degree. C., optionally
-10.degree. C. to 5.degree. C., optionally -5.degree. C. to
5.degree. C., or optionally 2.degree. C. to 8.degree. C. In one
non-limiting example, the thermal pack 9802 is in a refrigerated
condition for at least one month. In an implementation, sodium
acetate is used in the chemical in the chemical reaction thermal
pack 9802. Sodium acetate trihydrate crystals melt at 58.4.degree.
C., dissolving in water. When they are heated to around 100.degree.
C., and subsequently allowed to cool, the aqueous solution becomes
supersaturated. This solution is capable of cooling to room
temperature without forming crystals. When the supersaturated
solution is disrupted, crystals are formed. The bond-forming
process of crystallization is exothermic. The latent heat of fusion
is about 264-289 kJ/kg. The crystallization event can be triggered
by clicking on a metal disc, creating a nucleation center which
causes the solution to crystallize into solid sodium acetate
trihydrate again. This can be triggered by the pipette in the
system or other actuator in the device. Alternatively, a tip/needle
on the pipette with sodium acetate crystal on its surface can
puncture the sodium acetate foil seal. This will also trigger
crystallization. It should be understood that other exothermic
reactions can be used instead of sodium acetate and these other
reactions are not excluded. One non-limiting example is to use
magnesium/iron alloy in a porous matrix formed from polymeric
powders with sodium chloride incorporated. The reaction is started
by the addition of water. The water dissolves the sodium chloride
into an electrolyte solution causing magnesium and iron to function
as an anode and cathode, respectively. Optionally, an exothermic
oxidation-reduction reaction between the magnesium-iron alloy and
water can be used to produce magnesium hydroxide, hydrogen gas and
heat. Optionally, a fan or other flow generating device on the
system can be used to provide convective flow. The fan can be
placed to blow air to the underside of the cartridge, along the
sides, or optionally over the tops of the cartridge.
It should be understood that some cartridges 9800 may have more
than one heater. As seen in FIGS. 38A and 38B, a second thermal
device 9804 can also be a part of the cartridge 9800. In some
embodiments, the heaters 9802 and 9804 are sized and located to
thermally control temperature for certain areas of the cartridge
9800, particularly those vessels, wells, or other features that
contain materials that are sensitive to temperature or provide more
consistent or accurate results when they are used in certain
temperature ranges. As seen in FIGS. 38A and 38B, the heaters 9802
and 9804 are positioned to thermally condition (heat or cool) those
locations in the cartridge. In some embodiments, the heaters 9802
and 9804 are positioned to thermally condition particular reagents
in a cartridge. It should also be understood that thermally
conductive material such as but not limited to aluminum, copper, or
the like, may also be incorporated into the cartridge to
preferentially thermally condition certain areas of the cartridge.
In one non-limiting example, the thermally conductive materials
9806 and 9808 can be made of a material different from that of the
cartridge and be shaped to accommodate, contour, or otherwise be in
contact with or near certain pipette tips, reagent wells, diluent
wells, or the like. In some embodiments, the thermally conductive
material may be used to condition those areas that are spaced apart
from the thermal devices to more readily propagate thermal
conditioning to other areas of the cartridge. Optionally, the
thermally conductive material is located only at targeted areas
over the thermal packs and designed to only thermally condition
some but not other areas of the cartridge. Optionally, some
embodiments may integrate thermally conductive materials such as
but not limited to metal beads or other thermally conductive
materials into the polymeric or other material used to form the
cartridge. The cartridge can have isolated regions with temperature
control (e.g. a region with high temperature for nucleic acid
tests), without affecting other parts of the cartridge/device.
Referring now to FIG. 39, in another embodiment, the cartridge
receiving location 9830 with rails 9832 is configured to receive a
cartridge comprising a microfluidic cartridge 9810. This passive
flow cartridge 9810 may have one more sample deposit locations
9812. By way of non-limiting example, this cartridge 9810 may be a
microfluidic cartridge as described in U.S. Pat. Nos. 8,007,999 and
7,888,125, both fully incorporated herein by reference for all
purposes. The passive flow cartridge 9810 may also have one or more
rails that engage at least one slot 9832 of the cartridge receiving
location. The cartridge receiving location 9830 may also have one
more signal interface locations on the cartridge such as but not
limited to electrical connectors or optical connectors so that
electrodes, fiberoptics, or other elements in the cartridge can
communicate with corresponding equipment in the system that can
read signals from elements in the cartridge 9810.
It should be understood that a pipette may be used to load sample
into the cartridge 9810. Optionally, the passive flow cartridge
9810 may also be integrated for use with the pipette to transport
sample from certain ports in the cartridge 9810 to other ports on
the sample cartridge, to other cartridges, or to other types of
sample vessels. After the completion, the cartridge may be unloaded
from the cartridge receiving location 9830 as indicated by arrow
9819.
Referring now to FIG. 40, in a still further embodiment, the
cartridge receiving location 9830 with rails 9832 is configured to
receive a cartridge comprising a microfluidic portion 9822. In this
non-limiting example, the microfluidic portion 9822 is mounted on a
larger cartridge 9824 that can have various reagent region(s) 9826
and sample vessel region(s) 9828. Some embodiments may also have a
cartridge with sample vessel holding location 9938 that transports
the sample fluid in gas tight containers until they are ready for
analysis when loaded into the device. In one non-limiting example,
the sample being aliquoted into microfluidic portion 9822 may be
pre-treated by material in the sample vessel. In some embodiments,
the microfluidic portion 9822 can be moved to location separate
from the cartridge 9824 so that the processing on the microfluidic
portion 9822 can occur simultaneously with other sample processing
that may occur on the cartridge 9824. Optionally, the system may
have the microfluidic portion 9822 moved so that other reagents,
diluents, tips, or vessels that, in the present embodiment, are
housed below the microfluidic portion 9822, become accessible for
use. Optionally, the microfluidic portion 9822 may be returned to
the cartridge 9824 after use. The entire cartridge 9824 may use a
cover 9970 (not shown) to provide an enclosed unit for improved
cartridge handling when not in use in the system.
Referring now to FIG. 41, another embodiment of a cartridge
receiving location 9830 will now be described. This embodiment
shows a plurality of detector locations 9841 on a cartridge 9842. A
pipette 9844 can be used to transport sample to one or more the
detector locations 9841. In one non-limiting example, movement of
sample from one detector locations 9841 to another, or optionally,
from a sample vessel to one or more of the detector locations 9841
can be by way of the pipette 9844.
In one non-limiting example, the measurement of the sample at the
detector locations 9841 can be by way of a sensing electrode used
in one of two manners. First, the change can be detected with
respect to the exposed reference capacitor. In this embodiment, the
reference electrode is exposed to the same solution as the sensing
electrode. Optionally, a probe is designed to have similar
electrical characteristics as the affinity probed but not to bind
to a target in the solution in attached to the reference electrode.
A change in integrated charge is measured as binding occurs on the
sensing electrode (or affinity probe attached thereon) whose
electrical characteristics change, but not on the reference
electrode whose electrical characteristic remain the same. Second,
two measurements of the same electrode, before and after the
analyte binds, can be compared to establish the change in
integrated charge resulting from binding. In this case, the same
electrode at a previous time provides the reference. The device may
operate in differential detection mode, in which both reference and
sense electrode have attached affinity probes (of different
affinity) to reject common mode noise contributed by the matrix or
other noise sources.
In an alternative configuration, the reference electrode can be
configured so that the sensing electrode takes direct capacitance
measurements (non-differential). In this configuration, the
reference electrode can be covered with a small dielectric
substance such as epoxy or the device passivation or left exposed
to air. The signal from the electrode can then be compared to an
open circuit which establishes an absolute reference for
measurement but may be more susceptible to noise. Such an
embodiment uses the device in an absolute detection mode, in which
the reference is an unexposed (or exposed to a fix environment such
as air) fixed capacitor.
Referring now to FIGS. 42 to 45, it should be understood that in
some embodiments the thermal device is not integrated into a part
of a disposable such as cartridge 9800 but is instead a
non-disposable that is part of the hardware of the system. The
thermal device may be a thermal control unit. FIG. 42 shows one
embodiment of a cartridge 9820 that is received into an assay
station receiving location 9830 of the system. In some embodiments,
an assay station receiving location may be a tray. In this
non-limiting example, the assay station receiving location 9830 has
slots 9832 that are shaped to receive rails 9834 on the cartridge
9820. The cartridge 9820 is inserted into the assay station
receiving location 9830 until the cartridge 9820 engages a stop
9836. It should be understood that the regions in FIGS. 42-45 and
optionally in other cartridges described herein, the region may
contain a plurality of wells, tips or the like such as shown in the
cartridges of U.S. Pat. No. 8,088,593 fully incorporated herein by
reference for all purposes.
Referring now to FIG. 43 which shows an underside view of the assay
station receiving location 9830 which shows that there may be
convective flow devices 9840 positioned on the assay station
receiving location 9830 to facilitate flow in the underside of the
cartridge 9820 when it is in the desired location on the assay
station receiving location 9830. Although FIG. 43 shows the devices
9840 in only one location, it should be understood that devices
9840 may also be located at one or more other locations to access
other areas of the cartridge 9820. Some embodiments may configure
at least one of the convective devices 9840 to be pulling in air
while at least one other convective device 9840 is pushing air out
of the cartridge. There may be features such as but not limited to
vanes, fins, rods, tubes, or the like to guide air flow in the
underside or other areas of the cartridge 9820.
Referring now to FIG. 44, a cross-sectional view is shown of the
cartridge 9820 on the assay station receiving location 9830 that is
positioned over the convective flow device 9840. FIG. 44 further
shows that there is thermal device 9850 that is a non-disposable
that remains part of the system and is not disposed with the
cartridge. Alternatively, some embodiments may integrate the
thermal device 9850 into the cartridge, in which case the thermal
device 9850 is part of the disposable. As seen in FIG. 44, the
thermal device 9850 is at a first location spaced apart from the
targeted materials 9852 to be thermally conditioned in the
cartridge 9820. Referring still to FIG. 44, in some embodiments,
the underside of the cartridge is substantially enclosed except for
perhaps a hatch, door, or cover that allows for access to the
underside of the cartridge 9820.
Referring now to FIG. 45, this illustration shows that the thermal
device 9850 can be moved from the first location to a second
location to more directly contact the areas and/or components of
the cartridge 9820 to be thermally conditioned. As seen in FIG. 45,
the thermal device 9850 can have shapes such as but not limited to
cavities, openings, or the like that are contoured to engage
surfaces of the areas and/or components of the cartridge 9820 to be
thermally conditioned. It should be understood that the thermal
device 9850 can use various thermal elements to heat or cool the
portions that engage features of the cartridge or cartridge
components. In one non-limiting example, the thermal device 9850
may use heating rods 9852 in the device 9850. These may cause
thermal conditioning through electro-resistive heating or the like.
Thermal transfer may occur from corresponding cavities in
heater-block into each round-vessel bottom-stem through narrow
air-gap. The convective flow device 9840 may assist in accelerating
the thermal conditioning. Optionally, some embodiments may use the
convective flow device 9840 to bring steady state condition to the
cartridge sooner after an initial thermal conditioning phase. By
way of non-limiting example, a pre-heated heater block may be the
thermal device 9850 that engages with refrigerated (e.g. 4.degree.
C.) cartridge-round-vessels in the cartridge 9820, followed by
rapid heating from thermal device 9850, followed by fan-cooling by
convective flow device 9840, which then leads to controllable
operating temperature in vessels within about 180 seconds.
After thermally conditioning is completed or to provide better
access for the convective flow device 9840, the thermal device 9850
optionally returns to a location where it does not interfere with
the insertion and/or removal of the cartridge 9820 from the assay
station receiving location 9830, such as but not limited to
residing in recess 9858.
In some embodiments, a both a disposable such as a cartridge and
the hardware of the system contain a thermal device. In some
embodiments, a cartridge is not thermally conditioned prior to or
during use.
Optionally, the cartridge can also transform into different
configurations based on external or internal stimuli. The stimuli
can be sensed via sensors on the cartridge body, or be part of the
cartridge. More commonplace sensors such as RFID tags can also be
part of the cartridge. The cartridge can be equipped with biometric
sensors if, for example, the sample collection and analysis are
done in two separate locations (e.g. for patients in intensive
care, samples are collected from the patient and then transferred
to the device for analysis). This allows linking a patient sample
to the cartridge, thereby preventing errors. The cartridge could
have electric and/or fluidic interconnects to transfer signals
and/or fluids between different vessels, tips, etc. on the
cartridge. The cartridge can also comprise detectors and/or
sensors.
Intelligent cartridge design with feedback, self learning, and
sensing mechanisms enables a compact form factor with point of
service utility, waste reduction, and higher efficiencies.
In one embodiment, a separate external robotics system may be
available on site to assemble new cartridges in real time as they
are needed. Alternatively, this capability could be part of the
device or cartridge. Individual cartridge components for running
assays may include but are not limited to sealed vessels with
reagents, as well as tips and vessels for mixing and optical or
non-optical measurements. All or some of these components can be
added to a cartridge body in realtime by an automated robotic
system. The desired components for each assay can be loaded
individually onto a cartridge, or be pre-packaged into a
mini-cartridge. This mini-cartridge can then be added to the larger
cartridge which is inserted into the device. One or more assay
units, reagent units, tips, vessels or other components can be
added to a cartridge in real time. Cartridges may have no
components pre-loaded onto them, or may have some components
preloaded. Additional components can be added to a cartridge in
real time based on a patient order. The position of the components
added to a cartridge are predetermined and/or saved so that the
device protocol can properly execute the assay steps in the device.
The device may also configure the cartridge in real time if the
assay cartridge components are available to the device. For
example, tips and other cartridge components can be loaded into the
device, and loaded into cartridges in real time given the patient
order to the run at that time.
FIG. 2 shows an example of a device 200. A device may have a sample
collection unit 210. The device may include one or more support
structure 220, which may support one or more module 230a, 230b. The
device may include a housing 240, which may support or contain the
rest of the device. A device may also include a controller 250,
display 260, power unit 270, and communication unit 280. The device
may be capable of communicating with an external device 290 through
the communication unit. The device may have a processor and/or
memory that may be capable of effecting one or more steps or
providing instructions for one or more steps to be performed by the
device, and/or the processor and/or memory may be capable of
storing one or more instructions.
Sample Collection
A device may comprise a sample collection unit. The sample
collection unit may be configured to receive a sample from a
subject. The sample collection unit may be configured to receive
the sample directly from the subject or may be configured to
receive a sample indirectly that has been collected from the
subject.
One or more collection mechanisms may be used in the collection of
a sample from a subject. A collection mechanism may use one or more
principle in collecting the sample. For example, a sample
collection mechanism may use gravity, capillary action, surface
tension, aspiration, vacuum force, pressure differential, density
differential, thermal differential, or any other mechanism in
collecting the sample, or a combination thereof.
A bodily fluid may be drawn from a subject and provided to a device
in a variety of ways, including but not limited to, fingerstick,
lancing, injection, pumping, swabbing, pipetting, breathing, and/or
any other technique described elsewhere herein. The bodily fluid
may be provided using a bodily fluid collector. A bodily fluid
collector may include a lancet, capillary, tube, pipette, syringe,
needle, microneedle, pump, laser, porous membrane or any other
collector described elsewhere herein. The bodily fluid collector
may be integrated into a cartridge or onto the device, such as
through the inclusion of a lancet and/or capillary on the cartridge
body or vessel(s) or through a pipette that can aspirate a
biological sample from the patient directly. The collector may be
manipulated by a human or by automation, either directly or
remotely. One means of accomplishing automation or remote human
manipulation may be through the incorporation of a camera or other
sensing device onto the collector itself or the device or cartridge
or any component thereof and using the sensing device to guide the
sample collection.
In one embodiment, a lancet punctures the skin of a subject and
draws a sample using, for example, gravity, capillary action,
aspiration, pressure differential and/or vacuum force. The lancet,
or any other bodily fluid collector, may be part of the device,
part of a cartridge of the device, part of a system, or a stand
alone component. In another embodiment, a laser may be used to
puncture the skin or sever a tissue sample from a patient. The
laser may also be used to anesthetize the sample collection site.
In another embodiment, a sensor may measure optically through the
skin without invasively obtaining a sample. In some embodiments, a
patch may comprise a plurality of microneedles, which may puncture
the skin of a subject. Where needed, the lancet, the patch, or any
other bodily fluid collector may be activated by a variety of
mechanical, electrical, electromechanical, or any other known
activation mechanism or any combination of such methods.
In some instances, a bodily fluid collector may be a piercing
device that may be provided on a disposable or that may be
disposable. The piercing device may be used to convey a sample or
information about the sample to a non-disposable device that may
process the sample. Alternatively, the disposable piercing device
itself may process and/or analyze the sample.
In one example, a subject's finger (or other portion of the
subject's body) may be punctured to yield a bodily fluid. The
bodily fluid may be collected using a capillary tube, pipette,
swab, drop, or any other mechanism known in the art. The capillary
tube or pipette may be separate from the device and/or a cartridge
of the device that may be inserted within or attached to a device,
or may be a part of a device and/or cartridge. In another
embodiment where no active mechanism (beyond the body) is required,
a subject can simply provide a bodily fluid to the device and/or
cartridge, as for example, could occur with a saliva sample or a
finger-stick sample.
A bodily fluid may be drawn from a subject and provided to a device
in a variety of ways, including but not limited to, fingerstick,
lancing, injection, and/or pipetting. The bodily fluid may be
collected using venous or non-venous methods. The bodily fluid may
be provided using a bodily fluid collector. A bodily fluid
collector may include a lancet, capillary, tube, pipette, syringe,
venous draw, or any other collector described elsewhere herein. In
one embodiment, a lancet punctures the skin and draws a sample
using, for example, gravity, capillary action, aspiration, or
vacuum force. The lancet may be part of the reader device, part of
the cartridge, part of a system, or a stand alone component, which
can be disposable. Where needed, the lancet may be activated by a
variety of mechanical, electrical, electromechanical, or any other
known activation mechanism or any combination of such methods. In
one example, a subject's finger (or other portion of the subject's
body) may be punctured to yield a bodily fluid. Examples of other
portions of the subject's body may include, but is not limited to,
the subject's hand, wrist, arm, torso, leg, foot, ear, or neck. The
bodily fluid may be collected using a capillary tube, pipette, or
any other mechanism known in the art. The capillary tube or pipette
may be separate from the device and/or cartridge, or may be a part
of a device and/or cartridge or vessel. In another embodiment where
no active mechanism is required, a subject can simply provide a
bodily fluid to the device and/or cartridge, as for example, can
occur with a saliva sample. The collected fluid can be placed
within the device. A bodily fluid collector may be attached to the
device, removably attachable to the device, or may be provided
separately from the device.
In some embodiments, a sample may be provided directly to the
device, or may use an additional vessel or component that may be
used as a conduit or means for providing a sample to a device. In
one example, feces may be swabbed onto a cartridge or may be
provided to a vessel on a cartridge. In another example a urine cup
may snap out from a cartridge of a device, a device, or a
peripheral to a device. Alternatively, a small vessel may be pushed
out, snapped out, and/or twisted out of a cartridge of a device or
a peripheral to a cartridge. Urine may be provided directly to the
small vessel or from a urine cup. In another example, a nasal swab
may be inserted into a cartridge. A cartridge may include buffers
that may interact with the nasal swab. In some instances, a
cartridge may include one or more tanks or reservoirs with one or
more reagents, diluents, wash, buffers, or any other solutions or
materials. A tissue sample may be placed on a slide that may be
embedded within a cartridge to process the sample. In some
instances, a tissue sample may be provided to a cartridge through
any mechanism (e.g., opening, tray), and a slide may be
automatically prepared within the cartridge. A fluid sample may be
provided to a cartridge, and the cartridge may optionally be
prepared as a slide within the cartridge. Any description of
providing a sample to a cartridge or a vessel therein may also be
applied to providing the sample directly to the device without
requiring a cartridge. Any steps described herein as being
performed by the cartridge may be performed by the device without
requiring a cartridge.
A vessel for sample collection can be configured to obtain samples
from a broad range of different biological, environmental, and any
other matrices. The vessel can be configured to receive a sample
directly from a body part such as a finger or an arm by touching
the body part to the vessel. Samples may also be introduced through
sample transfer devices which may optionally be designed for
single-step processing in transferring a sample into a vessel or
cartridge or into the device. Collection vessels may be designed
and customized for each different sample matrix that is processed,
such as urine, feces, or blood. For example, a sealed vessel may
twist off of or pop out of a traditional urine cup so that it can
be placed directly in a cartridge without the need for pipetting a
sample. A vessel for sample collection can be configured to obtain
blood from a fingerstick (or other puncture site). The collection
vessel may be configured with one or more entry ports each
connected to one or more segregated chambers. The collection vessel
may be configured with only a single entry port connected to one of
more segregated chambers. The collected sample may flow into the
chambers via capillary action. Each segregated chamber may contain
one or more reagents. Each segregated chamber may contain different
reagents from the other chambers. Reagents in the chambers may be
coated on the chamber walls. The reagents may be deposited in
certain areas of the chambers, and/or in a graded fashion to
control reagent mixing and distribution in the sample. Chambers may
contain anticoagulants (for example, lithium-heparin, EDTA
(ethylenediaminetetraacetic acid), citrate). The chambers may be
arranged such that mixing of the sample among the various chambers
does not occur. The chambers may be arranged such that a defined
amount of mixing occurs among the various chambers. Each chamber
may be of the same or different size and/or volume. The chambers
can be configured to fill at the same or different rates with the
sample. The chambers may be connected to the entry port via an
opening or port that may have a valve. Such a valve may be
configured to permit fluid to flow in one or two directions. The
valve may be passive or active. The sample collection vessel may be
clear or opaque in certain regions. The sample collection vessel
may be configured to have one or more opaque regions to allow
automated and/or manual assessment of the sample collection
process. The sample in each chamber may be extracted by the device
by a sample handling system fitted with a tip or vessel to
interface with the sample collection vessel. The sample in each
chamber may be forced out of the chamber by a plunger. The samples
may be extracted or expelled from each chamber individually or
simultaneously.
A sample may be collected from an environment or any other source.
In some instances, the sample is not collected from a subject.
Examples of samples may include fluids (such as liquids, gas,
gels), solid, or semi-solid materials that may be tested. In one
scenario, a food product may be tested to determine whether the
food is safe to eat. In another scenario, an environmental sample
(e.g., water sample, soil sample, air sample) may be tested to
determine whether there are any contaminants or toxins. Such
samples can be collected using any mechanism, including those
described elsewhere herein. Alternatively, such samples can be
provided directly to the device, cartridge or to a vessel.
The collected fluid can be placed within the device. In some
instances, the collected fluid is placed within a cartridge of the
device. The collected fluid can be placed in any other region of
the device. The device may be configured to receive the sample,
whether it be directly from a subject, from a bodily fluid
collector, or from any other mechanism. A sample collection unit of
the device may be configured to receive the sample.
A bodily fluid collector may be attached to the device, removably
attachable to the device, or may be provided separately from the
device. In some instances, the bodily fluid collector is integral
to the device. The bodily fluid collector can be attached to or
removably attached to any portion of the device. The bodily fluid
collector may be in fluid communication with, or brought into fluid
communication with a sample collection unit of the device.
A cartridge may be inserted into the sample processing device or
otherwise interfaced with the device. The cartridge may be attached
to the device. The cartridge may be removed from the device. In one
example, a sample may be provided to a sample collection unit of
the cartridge. A cartridge may brought to a selected temperature
before being inserted into the device (e.g. to 4 C, room
temperature, 37 C, 40 C, 45 C, 50 C, 60 C, 70 C, 80 C, 90 C, etc.).
The sample may or may not be provided to the sample collection unit
via a bodily fluid collector. A bodily fluid collector may be
attached to the cartridge, removably attachable to the cartridge,
or may be provided separately from the cartridge. The bodily fluid
collector may or may not be integral to the sample collection unit.
The cartridge may then be inserted into the device. Alternatively,
the sample may be provided directly to the device, which may or may
not use the cartridge. The cartridge may comprise one or more
reagents, which may be used in the operation of the device. The
reagents may be self-contained within the cartridge. Reagents may
be provided to a device through a cartridge without requiring
reagents to be pumped into the device through tubes and/or tanks of
buffer. Alternatively, one or more reagents may already be provided
onboard the device. The cartridge may comprise a shell and
insertable tubes, vessels, or tips. The cartridge may contain, for
example, assay units, reagent units, processing units, or cuvettes
(for example, cytometry cuvettes). Vessels or tips may be used to
store reagents required to run tests. Some vessels or tips may be
preloaded onto cartridges. Other vessels or tips may be stored
within the device, possibly in a cooled environment as required. At
the time of testing, the device can assemble the on-board stored
vessels or tips with a particular cartridge as needed by use of a
robotic system within the device.
In some embodiments, a cartridge contains microfluidics channels.
Assays may be performed or detected within microfluidics channels
of a cartridge. Microfluidics channels of a cartridge have openings
to interface with, for example, tip, such that samples may be
loaded into or removed from the channel. In some embodiments,
samples and reagents may be mixed in a vessel, and then transferred
to a microfluidics channel of a cartridge. Alternatively, samples
and reagents may be mixed within a microfluidics channel of a
cartridge.
In some embodiments, a cartridge contains chips for electronic
microlfluidics applications. Small volumes of liquids may be
applied to such chips, and assay may be performed on the chips.
Liquids may be, for example, spotted or pipetted onto the chips,
and moved, for example by charge.
In some embodiments, a cartridge contains one or more assay units,
reagent units, or other vessels containing, for example,
antibodies, nucleic acid probes, buffers, chromogens,
chemiluminescent compounds, fluorescent compounds, washing
solutions, dyes, enzymes, salts, or nucleotides. In some
embodiments, a vessel may contain multiple different reagents in
the vessel (e.g. a buffer, a salt, and an enzyme in the same
vessel). The combination of multiple reagents in a single vessel
may be a reagent mixture. A reagent mixture may be, for example, in
liquid, gel, or lyophilized form. In some embodiments, one or more
or all of the vessels in a cartridge are sealed (e.g. a sealed
assay unit, reagent unit, etc.). The sealed vessels may be
individually sealed, they may all share the same seal (e.g. a
cartridge-wide seal), or groups of vessels may be sealed together.
Sealing materials may be, for example, a metal foil or a synthetic
material (e.g. polypropylene). The sealing material may be
configured to resist corrosion or degradation. In some embodiments,
a vessel may have a septum, such that the contents of the vessel
are not exposed to air without puncturing or transversing the
septum.
In some embodiments, a cartridge provided herein may contain all
the reagents necessary to perform one or more assays on-board the
cartridge. A cartridge may contain all of the reagents on-board
necessary to perform 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18,
20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60, 65, 70,
75, 80, 85, 90, 95, 100, or more assays. The assays may be any
assay or assay type disclosed elsewhere herein. In some
embodiments, a cartridge provided herein may contain within the
cartridge all the reagents necessary to perform all of the assays
to be performed on a biological sample from a subject. In some
embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22,
24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80,
85, 90, 95, 100, or more assays are to be performed in a biological
sample from a from a subject. A cartridge may also be configured to
receive or store a biological sample from a subject, such that all
of the reagents and biological material necessary to perform one or
more assays may be provided to a device through the insertion of a
cartridge containing the sample and reagents into the device. After
introduction of a sample into a device through a cartridge, a
sample may be, for example, stored in the device for archiving or
later analysis, or cultured in the device. In some embodiments, all
of the reagents in a cartridge are discretely packaged and/or
sealed from interfacing with hardware of a sample processing
device.
In some embodiments, provided herein is a system containing a
sample processing device and a cartridge. The system, sample
processing device, and cartridge may have any of the features
described elsewhere herein. The cartridge may be part of the sample
processing device. A cartridge may be positioned in a device or
module adjacent to a sensor (e.g. an optical sensor) or detection
station, such that reactions within the cartridge (e.g. in
microfluidics channels or vessels in the cartridge) may be
measured.
In some embodiments, in systems containing a sample processing
device and cartridge, the device stores some or all reagents for
performing assays within the device. For example, the device may
store common reagents such as water, selected buffers, and
detection-related compounds (e.g. chemiluminescent molecules and
chromogens) within the device. The device may direct reagents for
assays to the cartridge as needed. A device which stores reagents
may have tubing to transport reagents from reagent storage
locations to the cartridge. Storage of reagents within the device
may, in some situations, increase the speed of reactions or
decrease reagent waste.
In other embodiments, in systems containing a sample processing
device and cartridge, the device does not store any reagents for
performing assays within the device. Similarly, in some
embodiments, the device does not store any wash solutions or other
readily disposable liquids in the device. In such systems, a
cartridge containing all reagents on-board necessary to perform one
or more assays may be provided to the device. In some embodiments,
multiple reagents for performing a single assay may be provided in
a single fluidically isolated vessel (e.g. as a reaction mixture).
The device may use the reagents provided in the cartridge to
perform one or more assays with a biological sample. The biological
sample may also be included in the cartridge, or it may be
separately provided to the device. In addition, in some
embodiments, the device may return used reagents to the cartridge,
so that all reagents used for performing one or more assays both
enter and leave the device through the cartridge.
A sample processing device which does not store reagents within the
device (and instead, which receives reagents through the insertion
of a cartridge or other structure into the device) may have
advantages over a sample processing device which stores reagents or
other disposables within or in fluid communication with the device.
For example, a sample processing device which stores reagents
within the device may require complicated structures for storing
and transporting the reagents (e.g. storage areas and tubing).
These structures may increase the size of the device, require
regular maintenance, increase the total amount of reagents and
samples needed to perform assays, and introduce variables into
assays which may be a source of errors (for example, tubing may
lose its shape over time and not deliver accurate volumes). In
contrast, a sample processing device which does not store reagents
within or in fluid communication with the device may be smaller,
may require less maintenance, may use less reagents or sample to
perform assays, and may have higher accuracy, higher precision, and
lower coefficient of variation than a device which stores reagents.
In another example, typically, devices which store reagents in the
device can only contain a limited number of reagents, and thus, can
only perform a limited number of different assays. In addition,
such a device may only be configured to support assays with a
limited number of sample types (e.g. only blood or only urine).
Moreover, even if one or more of the reagents in the device could
be changed to support a different assay, changing of the reagent
may be a difficult and time-consuming processing (for example,
tubing containing a previous reagent may need to be washed to
prevent reagent carryover). In contrast, a sample processing device
which does not store reagents within or in fluid communication with
the device may be capable of performing a higher number of
different assays and of performing different assays more rapidly,
easily, and accurately than a device which stores reagents, for
example due to reduced or eliminated reagent cross-reactivity or
reduced or eliminated human intervention or calibration).
A bodily fluid collector or any other collection mechanism can be
disposable. For example, a bodily fluid collector can be used once
and disposed. A bodily fluid collector can have one or more
disposable components. Alternatively, a bodily fluid collector can
be reusable. The bodily fluid collector can be reused any number of
times. In some instances, the bodily fluid collector can include
both reusable and disposable components. To reduce the
environmental impact of disposal, the materials of the cartridge or
other bodily fluid collector may be manufactured of a compostable
or other "green" material.
Any component that is inserted into the system or device can be
identified based on identification tags or markings and/or other
communication means. Based on the identification of such
components, the system can ensure that said components are suitable
for use (e.g., not passed their expiration date). The system may
cross-reference with an on-board and/or remote databases containing
data and information concerning said components, or a related a
protocol or a patient ID.
Components inserted into the system or device may include on-boards
sensors. Such sensors may respond to temperature, humidity, light,
pressure, vibration, acceleration, and other environmental factors.
Such sensors may be sensitive to absolute levels, durations of
exposure levels, cumulative exposure levels, and other combinations
of factors. The system or device can read such sensors and/or
communicate with such sensors when the components are inserted into
the system or device or interface with the user interface to
determine how and if the said component(s) is suitable for use in
the system/device based on a set of rules.
A sample collection unit and/or any other portion of the device may
be capable of receiving a single type of sample, or multiple types
of samples. For example, the sample collection unit may be capable
of receiving two different types of bodily fluids (e.g., blood,
tears). In another example, the sample collection unit may be
capable of receiving two different types of biological samples
(e.g., urine sample, stool sample). Multiple types of samples may
or may not be fluids, solids, and/or semi-solids. For example, the
sample collection unit may be capable of accepting one or more of,
two or more of, or three or more of a bodily fluid, secretion
and/or tissue sample.
A device may be capable of receiving a single type of sample or
multiple types of samples. The device may be capable of processing
the single type of sample or multiple types of samples. In some
instances, a single bodily fluid collector may be used.
Alternatively, multiple and/or different bodily fluid collectors
may be used.
Sample
A sample may be received by the device. Examples of samples may
include various fluid samples. In some instances, the sample may be
a bodily fluid sample from the subject. The sample may be an
aqueous or gaseous sample. The sample may be a gel. The sample may
include one or more fluid component. In some instances, solid or
semi-solid samples may be provided. The sample may include tissue
collected from the subject. The sample may include a bodily fluid,
secretion, and/or tissue of a subject. The sample may be a
biological sample. The biological sample may be a bodily fluid, a
secretion, and/or a tissue sample. Examples of biological samples
may include but are not limited to, blood, serum, saliva, urine,
gastric and digestive fluid, tears, stool, semen, vaginal fluid,
interstitial fluids derived from tumorous tissue, ocular fluids,
sweat, mucus, earwax, oil, glandular secretions, breath, spinal
fluid, hair, fingernails, skin cells, plasma, nasal swab or
nasopharyngeal wash, spinal fluid, cerebral spinal fluid, tissue,
throat swab, biopsy, placental fluid, amniotic fluid, cord blood,
emphatic fluids, cavity fluids, sputum, pus, micropiota, meconium,
breast milk and/or other excretions. The sample may be provided
from a human or animal. The sample may be provided from a mammal,
vertebrate, such as murines, simians, humans, farm animals, sport
animals, or pets. The sample may be collected from a living or dead
subject.
The sample may be collected fresh from a subject or may have
undergone some form of pre-processing, storage, or transport. The
sample may be provided to a device from a subject without
undergoing intervention or much time. The subject may contact the
device, cartridge, and/or vessel to provide the sample.
A subject may provide a sample, and/or the sample may be collected
from a subject. A subject may be a human or animal. The subject may
be a mammal, vertebrate, such as murines, simians, humans, farm
animals, sport animals, or pets. The subject may be living or dead.
The subject may be a patient, clinical subject, or pre-clinical
subject. A subject may be undergoing diagnosis, treatment, and/or
disease management or lifestyle or preventative care. The subject
may or may not be under the care of a health care professional.
A sample may be collected from the subject by puncturing the skin
of the subject, or without puncturing the skin of the subject. A
sample may be collected through an orifice of the subject. A tissue
sample may be collected from the subject, whether it be an internal
or external tissue sample. The sample may be collected from any
portion of the subject including, but not limited to, the subject's
finger, hand, arm, shoulder, torso, abdomen, leg, foot, neck, ear,
or head.
In some embodiments, the sample may be an environmental sample.
Examples of environmental samples may include air samples, water
samples, soil samples, or plant samples.
Additional samples may include food products, beverages,
manufacturing materials, textiles, chemicals, therapies, or any
other samples.
One type of sample may be accepted and/or processed by the device.
Alternatively, multiple types of samples may be accepted and/or
processed by the device. For example, the device may be capable of
accepting one or more, two or more, three or more, four or more,
five or more, six or more, seven or more, eight or more, nine or
more, ten or more, twelve or more, fifteen or more, twenty or more,
thirty or more, fifty or more, or one hundred or more types of
samples. The device may be capable of accepting and/or processing
any of these numbers of sample types simultaneously and/or at
different times from different or the same matrices. For example,
the device may be capable of preparing, assaying and/or detecting
one or multiple types of samples.
Any volume of sample may be provided from the subject or from
another source. Examples of volumes may include, but are not
limited to, about 10 mL or less, 5 mL or less, 3 mL or less, 1
.mu.L or less, 500 .mu.L or less, 300 .mu.L or less, 250 .mu.L or
less, 200 .mu.L or less, 170 .mu.L or less, 150 .mu.L or less, 125
.mu.L or less, 100 .mu.L or less, 75 .mu.L or less, 50 .mu.L or
less, 25 .mu.L or less, 20 .mu.L or less, 15 .mu.L or less, 10
.mu.L or less, 5 .mu.L or less, 3 .mu.L or less, 1 .mu.L or less,
500 nL or less, 250 nL or less, 100 nL or less, 50 nL or less, 20
nL or less, 10 nL or less, 5 nL or less, 1 nL or less, 500 pL or
less, 100 pL or less, 50 pL or less, or 1 pL or less. The amount of
sample may be about a drop of a sample. The amount of sample may be
about 1-5 drops of sample, 1-3 drops of sample, 1-2 drops of
sample, or less than a drop of sample. The amount of sample may be
the amount collected from a pricked finger or fingerstick. Any
volume, including those described herein, may be provided to the
device.
Sample to Device
A sample collection unit may be integral to the device. The sample
collection unit may be separate from the device. In some
embodiments, the sample collection unit may be removable and/or
insertable from the device. The sample collection unit may or may
not be provided in a cartridge. A cartridge may or may not be
removable and/or insertable from the device.
A sample collection unit may be configured to receive a sample. The
sample collection unit may be capable of containing and/or
confining the sample. The sample collection unit may be capable of
conveying the sample to another portion of the device.
The sample collection unit may be in fluid communication with one
or more module of a device. In some instances, the sample
collection unit may be permanent fluid communication with one or
more module of the device. Alternatively, the sample collection
unit may be brought into and/or out of fluid communication with a
module. The sample collection unit may or may not be selectively
fluidically isolated from one or more module. In some instances,
the sample collection unit may be in fluid communication with each
of the modules of the device. The sample collection unit may be in
permanent fluid communication with each of the modules, or may be
brought into and/or out of fluid communication with each
module.
A sample collection unit may be selectively brought into and/or out
of fluid communication with one or more modules. The fluid
communication may be controlled in accordance with one or more
protocol or set of instructions. A sample collection unit may be
brought into fluid communication with a first module and out of
fluid communication with a second module, and vice versa.
Similarly, the sample collection unit may be in fluid communication
with one or more component of a device. In some instances, the
sample collection unit may be in permanent fluid communication with
one or more component of the device. Alternatively, the sample
collection unit may be brought into and/or out of fluid
communication with a device component. The sample collection unit
may or may not be selectively fluidically isolated from one or more
component. In some instances, the sample collection unit may be in
fluid communication with each of the components of the device. The
sample collection unit may be in permanent fluid communication with
each of the components, or may be brought into and/or out of fluid
communication with each component.
One or more mechanisms may be provided for transferring a sample
from the sample collection unit to a test site. In some
embodiments, flow-through mechanisms may be used. For example, a
channel or conduit may connect a sample collection unit with a test
site of a module. The channel or conduit may or may not have one or
more valves or mechanisms that may selectively permit or obstruct
the flow of fluid.
Another mechanism that may be used to transfer a sample from a
sample collection unit to a test site may use one or more
fluidically isolated component. For example, a sample collection
unit may provide the sample to one or more tip or vessel that may
be movable within the device. The one or more tip or vessel may be
transferred to one or more module. In some embodiments, the one or
more tip or vessel may be shuttled to one or more module via a
robotic arm or other component of the device. In some embodiments,
the tip or vessel may be received at a module. In some embodiments,
a fluid handling mechanism at the module may handle the tip or
vessel. For example, a pipette at a module may pick up and/or
aspirate a sample provided to the module.
A device may be configured to accept a single sample, or may be
configured to accept multiple samples. In some instances, the
multiple samples may or may not be multiple types of samples. For
example, in some instances a single device may handle a single
sample at a time. For example, a device may receive a single
sample, and may perform one or more sample processing step, such as
a sample preparation step, assay step, and/or detection step with
the sample. The device may complete processing or analyzing a
sample, before accepting a new sample.
In another example, a device may be capable of handling multiple
samples simultaneously. In one example, the device may receive
multiple samples simultaneously. The multiple samples may or may
not be multiple types of samples. Alternatively, the device may
receive samples in sequence. Samples may be provided to the device
one after another, or may be provided to device after any amount of
time has passed. A device may be capable of beginning sample
processing on a first sample, receiving a second sample during said
sample processing, and process the second sample in parallel with
the first sample. The first and second sample may or may not be the
same type of sample. The device may be able to parallel process any
number of samples, including but not limited to more than and/or
equal to about one sample, two samples, three samples, four
samples, five samples, six samples, seven samples, eight samples,
nine samples, ten samples, eleven samples, twelve samples, thirteen
samples, fourteen samples, fifteen samples, sixteen samples,
seventeen samples, eighteen samples, nineteen samples, twenty
samples, twenty-five samples, thirty samples, forty samples, fifty
samples, seventy samples, one hundred samples.
In some embodiments, a device may comprise one, two or more modules
that may be capable of processing one, two or more samples in
parallel. The number of samples that can be processed in parallel
may be determined by the number of available modules and/or
components in the device.
When a plurality of samples is being processed simultaneously, the
samples may begin and/or end processing at any time. The samples
need not begin and/or end processing at the same time. A first
sample may have completed processing while a second sample is still
being processed. The second sample may begin processing after the
first sample has begun processing. As samples have completed
processing, additional samples may be added to the device. In some
instances, the device may be capable of running continuously with
samples being added to the device as various samples have completed
processing.
The multiple samples may be provided simultaneously. The multiple
samples may or may not be the same type of sample. For example,
multiple sample collection units may be provided to a device. For
example, one, two or more lancets may be provided on a device or
may be brought into fluid communication with a sample collection
unit of a device. The multiple sample collection units may receive
samples simultaneously or at different times. Multiple of any of
the sample collection mechanisms described herein may be used. The
same type of sample collection mechanisms, or different types of
sample collection mechanisms may be used.
The multiple samples may be provided in sequence. In some
instances, multiple sample collection units, or single sample
collection units may be used. Any combination of sample collection
mechanisms described herein may be used. A device may accept one
sample at a time, two samples at a time, or more. Samples may be
provided to the device after any amount of time has elapsed.
Modules
Devices may comprise one or more module. A module may be capable of
performing one or more, two or more, or all three of a sample
preparation step, assay step, and/or detection step. FIG. 3 shows
an example of a module 300. A module may comprise one or more, two
or more, or three or more of a sample preparation station 310,
and/or an assay station 320, and/or a detection station 330. In
some embodiments, multiple of a sample preparation station, assay
station, and/or detection station are provided. A module may also
include a fluid handling system 340.
A module may include one or more sample preparation station. A
sample preparation station may include one or more component
configured for chemical processing and/or physical processing.
Examples of such sample preparation processes may include dilution,
concentration/enrichment, separation, sorting, filtering, lysing,
chromatography, incubating, or any other sample preparation step. A
sample preparation station may include one or more sample
preparation components, such as a separation system (including, but
not limited to, a centrifuge), magnets (or other magnetic
field-inducing devices) for magnetic separation, a filter, a
heater, or diluents.
A sample preparation station may be insertable into or removable
from a system, device, or module. A sample preparation station may
comprise a cartridge. In some embodiments, any description of a
cartridge provided herein may apply to a sample preparation
station, and vice-versa.
One or more assay station may be provided to a module. The assay
station may include one or more component configured to perform one
or more of the following assays or steps: immunoassay, nucleic acid
assay, receptor-based assay, cytometric assay, colorimetric assay,
enzymatic assay, electrophoretic assay, electrochemical assay,
spectroscopic assay, chromatographic assay, microscopic assay,
topographic assay, calorimetric assay, turbidimetric assay,
agglutination assay, radioisotope assay, viscometric assay,
coagulation assay, clotting time assay, protein synthesis assay,
histological assay, culture assay, osmolarity assay, and/or other
types of assays or combinations thereof. The assay station may be
configured for proteinaceous assay, including immunoassay and
Enzymatic assay or any other assay that involves interaction with a
proteinaceous component. Topographic assays in some cases include
morphological assays. Examples of other components that may be
included in an assay station or a module are, without limitation,
one or more of the following: temperature control unit, heater,
thermal block, cytometer, electromagnetic energy source (e.g.,
x-ray, light source), assay units, reagent units, and/or supports.
In some embodiments, a module includes one or more assay stations
capable of performing nucleic acid assay and proteinaceous assay
(including immunoassay and enzymatic assay). In some embodiments, a
module includes one or more assay stations capable of performing
fluorescent assay and cytometry.
An assay station may be insertable into or removable from a system,
device, or module. An assay station may comprise a cartridge. In
some embodiments, any description of an assay/reagent unit support
or cartridge provided herein may apply to an assay station, and
vice-versa.
In some embodiments, a system, device, or module provided herein
may have an assay station/cartridge receiving location. The assay
station receiving location may be configured to receive a removable
or insertable assay station. The assay station receiving location
may be situated in the module, device, or system such that an assay
station positioned in the receiving location (and assay units
therein) may be accessible by a sample handling system of the
module, device, or system. The assay station receiving location may
be configured to position an assay station at a precise location
within the receiving location, such that a sample handling system
may accurately access components of the assay station. An assay
station receiving location may be a tray. The tray may be movable,
and may have multiple positions, for example, a first position
where the tray extends outside of the housing of the device, and a
second position wherein the tray is inside of the housing of the
device. In some embodiments, an assay station may be locked in
place in an assay station receiving location. In some embodiments,
the assay station receiving location may contain or be operatively
coupled to a thermal control unit to regulate the temperature of
the assay station. In some embodiments, the assay station receiving
location may contain or be operatively coupled to a detector (e.g.
bar code detector, RFID detector) for an identifier (e.g. bar code,
RFID tag) which may be on an assay station. The identifier detector
may be in communication with a controller or other component of the
device, such that the identifier detector can transmit information
regarding the identity of an assay station/cartridge inserted into
the device to the device or system controller.
The assay station may or may not be located separately from the
preparation station. In some instances, an assay station may be
integrated within the preparation station. Alternatively, they may
be distinct stations, and a sample or other substance may be
transmitted from one station to another.
Assay units may be provided, and may have one or more
characteristics as described further elsewhere herein. Assay units
may be capable of accepting and/or confining a sample. The assay
units may be fluidically isolated from or hydraulically independent
of one another. In some embodiments, assay units may have a tip
format. An assay tip may have an interior surface and an exterior
surface. The assay tip may have a first open end and a second open
end. In some embodiments, assay units may be provided as an array.
Assay units may be movable. In some embodiments, individual assay
units may be movable relative to one another and/or other
components of the device. In some instances, one or a plurality of
assay units may be moved simultaneously. In some embodiments, an
assay unit may have a reagent or other reactant coated on a
surface. In some embodiments, a succession of reagents may be
coated or deposited on a surface, such as a tip surface, and the
succession of reagents can be used for sequential reactions.
Alternatively, assay units may contain beads or other surfaces with
reagents or other reactants coated thereon or absorbed, adsorbed or
adhered therein. In another example, assay units may contain beads
or other surfaces coated with or formed of reagents or other
reactants that may dissolve. In some embodiments, assay units may
be cuvettes. In some instances, cuvettes may be configured for
cytometry, may include microscopy cuvettes.
Reagent units may be provided and may have one or more
characteristics as described further elsewhere herein. Reagent
units may be capable of accepting and/or confining a reagent or a
sample. Reagent units may be fluidically isolated from or
hydraulically independent of one another. In some embodiments,
reagent units may have a vessel format. A reagent vessel may have
an interior surface and an exterior surface. The reagent unit may
have an open end and a closed end. In some embodiments, the reagent
units may be provided as an array. Reagent units may be movable. In
some embodiments, individual reagent units may be movable relative
to one another and/or other components of the device. In some
instances, one or a plurality of reagent units may be moved
simultaneously. A reagent unit can be configured to accept one or
more assay unit. The reagent unit may have an interior region into
which an assay unit can be at least partially inserted.
A support may be provided for the assay units and/or reagent units.
In some embodiments, the support may have an assay station format,
a cartridge format or a microcard format. In some embodiments a
support may have a patch format or may be integrated into a patch
or an implantable sensing an analytical unit. One or more
assay/reagent unit support may be provided within a module. The
support may be shaped to hold one or more assay units and/or
reagent units. The support may keep the assay units and/or reagent
units aligned in a vertical orientation. The support may permit
assay units and/or reagent units to be moved or movable. Assay
units and/or reagent units may be removed from and/or placed on a
support. The device and/or system may incorporate one or more
characteristics, components, features, or steps provided in U.S.
Patent Publication No. 2009/0088336, which is hereby incorporated
by reference in its entirety.
A module may include one or more detection stations. A detection
station may include one or more sensors that may detect
visual/optical signals, infra-red signals, heat/temperature
signals, ultraviolet signals, any signal along an electromagnetic
spectra, electric signals, chemical signals, audio signals,
pressure signals, motion signals, or any other type of detectable
signals. The sensors provided herein may or may not include any of
the other sensors described elsewhere herein. The detection station
may be located separately from the sample preparation and/or assay
station. Alternatively, the detection station may be located in an
integrated manner with the sample preparation and/or assay station.
A detection station may contain one or more detection units,
including any detection unit disclosed elsewhere herein. A
detection station may contain, for example, a spectrophotometer, a
PMT, a photodiode, a camera, an imaging device, a CCD or CMOS
optical sensor, or a non-optical sensor. In some embodiments, a
detection station may contain a light source and optical sensor. In
some embodiments, a detection station may contain a microscope
objective and an imaging device.
In some embodiments, a sample may be provided to one or more sample
preparation station before being provided to an assay station. In
some instances, a sample may be provided to a sample preparation
after being provided to an assay station. A sample may undergo
detection before, during, or after it is provided to a sample
preparation station and/or assay station.
A fluid handling system may be provided to a module. The fluid
handling system may permit the movement of a sample, reagent, or a
fluid. The fluid handling system may permit the dispensing and/or
aspiration of a fluid. The fluid handling system may pick up a
desired fluid from a selected location and/or may dispense a fluid
at a selected location. The fluid handling system may permit the
mixing and/or reaction of two or more fluids. In some cases, a
fluid handling mechanism may be a pipette. Examples of pipettes or
fluid handling mechanisms are provided in greater detail elsewhere
herein.
Any description herein of a fluid handling system may also apply to
other sample handling systems, and vice versa. For example, a
sample handling system may transport any type of sample, including
but not limited to bodily fluids, secretions, or tissue samples. A
sample handling system may be capable of handling fluids, solids,
or semi-solids. A sample handling system may be capable of
accepting, depositing, and/or moving a sample, and/or any other
substance within the device may be useful and/or necessary for
sample processing within the device. A sample handling system may
be capable of accepting, depositing, and/or moving a container
(e.g., assay unit, reagent unit) that may contain a sample, and/or
any other substance within the device.
A fluid handling system may include a tip. For example, a pipette
tip may be removably connected to a pipette. The tip may interface
with a pipette nozzle. Examples of tip/nozzle interfaces are
provided in greater detail elsewhere herein.
Another example of a fluid handling system may use flow-through
designs. For example, a fluid handling system may incorporate one
or more channels and/or conduits through which a fluid may flow.
The channel or conduit may comprise one or more valves that may
selectively stop and/or permit the flow of fluid.
A fluid handling system may have one or more portion that may
result in fluid isolation. For example, a fluid handling system may
use a pipette tip that may be fluidically isolated from other
components of the device. The fluidically isolated portions may be
movable. In some embodiments, the fluid handling system tips may be
assay tips as described elsewhere herein.
A module may have a housing and/or support structure. In some
embodiments, a module may have a support structure upon which one
or more component of the module may rest. The support structure may
support the weight of one or more component of the module. The
components may be provided above the support structure, on the side
of the support structure, and/or under the support structure. The
support structure may be a substrate which may connect and/or
support various components of the module. The support structure may
support one or more sample preparation station, assay station,
and/or detection station of the module. A module may be
self-contained. The modules may be moved together. The various
components of the module may be capable of being moved together.
The various components of the module may be connected to one
another. The components of the module may share a common
support.
A module may be enclosed or open. A housing of the module may
enclose the module therein. The housing may completely enclose the
module or may partially enclose the module. The housing may form an
air-tight enclosure around the module. Alternatively, the housing
need not be air-tight. The housing may enable the temperature,
humidity, pressure, or other characteristics within the module or
component(s) of the module to be controlled.
Electrical connections may be provided for a module. A module may
be electrically connected to the rest of the device. A plurality of
modules may or may not be electrically connected to one another. A
module may be brought into electrical connection with a device when
a module is inserted/attached to the device. The device may provide
power (or electricity) to the module. A module may be disconnected
from the electrical source when removed from the device. In one
instance, when a module is inserted into the device, the module
makes an electrical connection with the rest of the device. For
example, the module may plug into the support of a device. In some
instances, the support (e.g., housing) of the device may provide
electricity and/or power to the module.
A module may also be capable of forming fluidic connections with
the rest of the device. In one example, a module may be fluidically
connected to the rest of the device. Alternatively, the module may
be brought into fluidic communication with the rest of the device
via, e.g., a fluid handling system disclosed herein. The module may
be brought into fluidic communication when the module is
inserted/attached to the device, or may be selectively brought into
fluidic communication anytime after the module is inserted/attached
to the device. A module may be disconnected from fluidic
communication with the device when the module is removed from the
device and/or selectively while the module is attached to the
device. In one example, a module may be in or may be brought into
fluidic communication with a sample collection unit of the device.
In another example, a module may be in or may be brought into
fluidic communication with other modules of the device.
A module may have any size or shape, including those described
elsewhere herein. A module may have a size that is equal to, or
smaller than the device. The device module may enclose a total
volume of less than or equal to about 4 m.sup.3, 3 m.sup.3, 2.5
m.sup.3, 2 m.sup.3, 1.5 m.sup.3, 1 m.sup.3, 0.75 m.sup.3, 0.5
m.sup.3, 0.3 m.sup.3, 0.2 m.sup.3, 0.1 m.sup.3, 0.08 m.sup.3, 0.05
m.sup.3, 0.03 m.sup.3, 0.01 m.sup.3, 0.005 m.sup.3, 0.001 m.sup.3,
500 cm.sup.3, 100 cm.sup.3, 50 cm.sup.3, 10 cm.sup.3, 5 cm.sup.3, 1
cm.sup.3, 0.5 cm.sup.3, 0.1 cm.sup.3, 0.05 cm.sup.3, 0.01 cm.sup.3,
0.005 cm.sup.3, or 0.001 cm.sup.3. The module may have any of the
volumes described elsewhere herein.
The module and/or module housing may have a footprint covering a
lateral area of the device. In some embodiments, the device
footprint may be less than or equal to about 4 m.sup.2, 3 m.sup.2,
2.5 m.sup.2, 2 m.sup.2, 1.5 m.sup.2, 1 m.sup.2, 0.75 m.sup.2, 0.5
m.sup.2, 0.3 m.sup.2, 0.2 m.sup.2, 0.1 m.sup.2, 0.08 m.sup.2, 0.05
m.sup.2, 0.03 m.sup.2, 100 cm.sup.2, 80 cm.sup.2, 70 cm.sup.2, 60
cm.sup.2, 50 cm.sup.2, 40 cm.sup.2, 30 cm.sup.2, 20 cm.sup.2, 15
cm.sup.2, 10 cm.sup.2, 7 cm.sup.2, 5 cm.sup.2, 1 cm.sup.2, 0.5
cm.sup.2, 0.1 cm.sup.2, 0.05 cm.sup.2, 0.01 cm.sup.2, 0.005
cm.sup.2, or 0.001 cm.sup.2.
The module and/or module housing may have a lateral dimension
(e.g., width, length, or diameter) or a height less than or equal
to about 4 m, 3 m, 2.5 m, 2 m, 1.5 m, 1.2 m, 1 m, 80 cm, 70 cm, 60
cm, 50 cm, 40 cm, 30 cm, 25 cm, 20 cm, 15 cm, 12 cm, 10 cm, 8 cm, 5
cm, 3 cm, 1 cm, 0.5 cm, 0.1 cm, 0.05 cm, 0.01 cm, 0.005 cm, or
0.001 cm. The lateral dimensions and/or height may vary from one
another. Alternatively, they may be the same. In some instances,
the module may be tall and thin, or may be short and squat. The
height to lateral dimension ratio may be greater than or equal to
100:1, 50:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1,
2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30,
1:50, or 1:100. The module and/or the module housing may
proportionally be tall and thin.
The module and/or module housing may have any shape. In some
embodiments, the module may have a lateral cross-sectional shape of
a rectangle or square. In other embodiments, the module may have a
lateral cross-sectional shape of a circle, ellipse, triangle,
trapezoid, parallelogram, pentagon, hexagon, octagon, or any other
shape. The module may have a vertical cross-sectional shape of a
circle, ellipse, triangle, rectangle, square, trapezoid,
parallelogram, pentagon, hexagon, octagon, or any other shape. The
module may or may not have a box-like shape.
Any number of modules may be provided for a device. A device may be
configured to accept a fixed number of modules. Alternatively, the
device may be configured to accept a variable number of modules. In
some embodiments, each module for the device may have the same
components and/or configurations. Alternatively, different modules
for the device may have varying components and/or configurations.
In some instances, the different modules may have the same housing
and/or support structure formats. In another example, the different
modules may still have the same overall dimensions. Alternatively,
they may have varying dimensions.
In some instances a device may have a single module. The single
module may be configured to accept a single sample at once, or may
be capable of accepting a plurality of samples simultaneously or in
sequence. The single module may be capable of performing one or
more sample preparation step, assay step, and/or detection step.
The single module may or may not be swapped out to provide
different functionality.
Further details and descriptions of modules and module components
are described further elsewhere herein. Any such embodiments of
such modules may be provided in combination with others or
alone.
Racks
In an aspect of the invention, a system having a plurality of
modules is provided. The system is configured to assay a biological
sample, such as a fluid and/or tissue sample from a subject.
In some embodiments, the system comprises a plurality of modules
mounted on a support structure. In an embodiment, the support
structure is a rack having a plurality of mounting stations, an
individual mounting station of the plurality of mounting stations
for supporting a module.
In an embodiment, the rack comprises a controller communicatively
coupled to the plurality of modules. In some situations, the
controller is communicatively coupled to a fluid handling system,
as described below. The controller is configured to control the
operation of the modules to prepare and/or process a sample, such
as to assay a sample via one or more of the techniques described
herein.
An individual module of the plurality of modules comprises a sample
preparation station, assay station, and/or detection station. The
system is configured to perform (a) multiple sample preparation
procedures selected from the group consisting of sample processing,
centrifugation, separation, physical separation and chemical
separation, and (b) at least one type of assay selected from the
group consisting of immunoassay, nucleic acid assay, receptor-based
assay, cytometric assay, colorimetric assay, enzymatic assay,
electrophoretic assay, electrochemical assay, spectroscopic assay,
chromatographic assay, microscopic assay, topographic assay,
calorimetric assay, turbidimetric assay, agglutination assay,
radioisotope assay, viscometric assay, coagulation assay, clotting
time assay, protein synthesis assay, histological assay, culture
assay, osmolarity assay, and/or other types of assays or
combinations thereof. In some embodiments, separation includes
magnetic separation, such as, e.g., separation with the aid of a
magnetic field.
In an embodiment, the support structure is a rack-type structure
for removably holding or securing an individual module of the
plurality of modules. The rack-type structure includes a plurality
of bays configured to accept and removably secure a module. In one
example, as shown in FIG. 4, a rack 400 may have one or more
modules 410a, 410b, 410c, 410d, 410e, 410f. The modules may have a
vertical arrangement where they are positioned over one another.
For example, six modules may be stacked on top of one another. The
modules may have a horizontal arrangement where they are adjacent
to one another. In another example, the modules may form an array.
FIG. 5 illustrates an example of a rack 500 having a plurality of
modules 510 that form an array. For example, the modules may form a
vertical array that is M modules high and/or N modules wide,
wherein M, N are positive whole numbers. In other embodiments, a
rack may support an array of modules, where a horizontal array of
modules is formed. For example, the modules may form a horizontal
array that is N modules wide and/or P modules long, wherein N and P
are positive whole numbers. In another example, a three-dimensional
array of modules may be supported by a rack, where the modules form
a block that is M modules high, N modules wide, and P modules long,
where M, N, and P are positive whole numbers. A rack may be able to
support any number of modules having any number of
configurations.
In some embodiments, racks may have one or more bays, each bay
configured to accept one or more module. A device may be capable of
operating when a bay has accepted a module. A device may be capable
of operating even if one or more bays have not accepted a
module.
FIG. 6 shows another embodiment of a rack mounting configuration.
One or more module 600a, 600b may be provided adjacent to one
another. Any numbers of modules may be provided. For example, the
modules may be vertically stacked atop one another. For instances,
N modules may be vertically stacked on top of one another, where N
is any positive whole number. In another example, the modules may
be horizontally connected to one another. Any combination of
vertical and/or horizontal connections between modules may be
provided. The modules may directly contact one another or may have
a connecting interface. In some instances, modules may be added or
removed from the stack/group. The configuration may be capable of
accommodating any number of modules. In some embodiments, the
number of modules may or may not be restricted by a device
housing.
In another embodiment, the support structure is disposed below a
first module and successive modules are mountable on one another
with or without the aid of mounting members disposed on each
module. The mounting members may be connecting interfaces between
modules. In an example, each module includes a magnetic mounting
structure for securing a top surface of a first module to a bottom
surface to a second module. Other connecting interfaces may be
employed, which may include magnetic features, adhesives, sliding
features, locking features, ties, snap-fits, hook-and-loop
fasteners, twisting features, or plugs. The modules may be
mechanically and/or electrically connected to one another. In such
fashion, modules may be stacked on one or next to another to form a
system for assaying a sample.
In other embodiments, a system for assaying a sample comprises a
housing and a plurality of modules within the housing. In an
embodiment, the housing is a rack having a plurality of mounting
stations, an individual mounting station of the plurality of
mounting stations for supporting a module. For example, a rack may
be integrally formed with the housing. Alternatively, the housing
may contain or surround the rack. The housing and the rack may or
may not be formed of separate pieces that may or may not be
connected to one another. An individual module of the plurality of
modules comprises at least one station selected from the group
consisting of a sample preparation station, assay station and
detection station. The system comprises a fluid handling system
configured to transfer a sample or reagent vessel within the
individual module or from the individual module to another module
within the housing of the system. In an embodiment, the fluid
handling system is a pipette.
In some embodiments, all modules could be shared within a device or
between devices. For example, a device may have one, some or all of
its modules as specialized modules. In this case, a sample may be
transported from one module to another module as need be. This
movement may be sequential or random.
Any of the modules can be a shared resource or may comprise
designated shared resources. In one example a designated shared
resource may be a resource not available to all modules, or that
may be available in limited numbers of modules. A shared resource
may or may not be removable from the device. An example of a shared
resource may include a cytometry station.
In an embodiment, the system further comprises a cytometry station
for performing cytometry on one or more samples. The cytometry
station may be supported by the rack and operatively coupled to
each of the plurality of modules by a sample handling system.
Cytometry assays are typically used to optically measure
characteristics of individual cells. The cells being monitored may
be live and/or dead cells. By using appropriate dyes, stains, or
other labeling molecules, cytometry may be used to determine the
presence, quantity, and/or modifications of specific proteins,
nucleic acids, lipids, carbohydrates, or other molecules.
Properties that may be measured by cytometry also include measures
of cellular function or activity, including but not limited to
phagocytosis, active transport of small molecules, mitosis or
meiosis; protein translation, gene transcription, DNA replication,
DNA repair, protein secretion, apoptosis, chemotaxis, mobility,
adhesion, antioxidizing activity, RNAi, protein or nucleic acid
degradation, drug responses, infectiousness, and the activity of
specific pathways or enzymes. Cytometry may also be used to
determine information about a population of cells, including but
not limited to cell counts, percent of total population, and
variation in the sample population for any of the characteristics
described above. The assays described herein may be used to measure
one or more of the above characteristics for each cell, which may
be advantageous to determining correlations or other relationships
between different characteristics. The assays described herein may
also be used to independently measure multiple populations of
cells, for example by labeling a mixed cell population with
antibodies specific for different cell lines.
Cytometry may be useful for determining characteristics of cells in
real-time. Characteristics of cells may be monitored continuously
and/or at different points in time. The different points in time
may be at regular or irregular time intervals. The different points
in time may be in accordance with a predetermined schedule or may
be triggered by one or more event. Cytometry may use one or more
imaging or other sensing technique described herein to detect
change in cells over time. This may include cell movement or
morphology. Kinematics or dynamics of a sample may be analyzed.
Time series analysis may be provided for the cells. Such real-time
detection may be useful for calculation of agglutination,
coagulation, or prothrombin time. The presence of one or more
molecule and/or disease, response to a disease and/or drug, may be
ascertained based on the time-based analysis.
In an example, cytometric analysis is by flow cytometry or by
microscopy. Flow cytometry typically uses a mobile liquid medium
that sequentially carries individual cells to an optical detector.
Microscopy typically uses optical means to detect stationary cells,
generally by recording at least one magnified image. For
microscopy, the stationary cells may be in a microscopy cuvette or
slide, which may be positioned on a microscopy stage adjacent to or
in optical connection with an imaging device for detecting the
cells. Imaged cells may be, for example, counted or measured for
one or more antigens or other features. It should be understood
that flow cytometry and microscopy are not entirely exclusive. As
an example, flow cytometry assays use microscopy to record images
of cells passing by the optical detector. Many of the targets,
reagents, assays, and detection methods may be the same for flow
cytometry and microscopy. As such, unless otherwise specified, the
descriptions provided herein should be taken to apply to these and
other forms of cytometric analyses known in the art.
In some embodiments, up to about 10,000 cells of any given type may
be measured. In other embodiments, various numbers of cells of any
given type are measured, including, but not limited to, more than,
and/or equal to about 10 cells, 30 cells, 50 cells, 100 cells, 150
cells, 200 cells, 300 cells, 500 cells, 700 cells, 1000 cells, 1500
cells, 2000 cells, 3000 cells, 5000 cells, 6000 cells, 7000 cells,
8000 cells, 9000 cells, 10000 cells, 100,000 cells, 500,000 cells,
1,000,000 cells, 5,000,000 cells, or 10,000,000 cells.
In some embodiments, cytometry is performed in microfluidic
channels. For instance, flow cytometry analyses are performed in a
single channel or in parallel in multiple channels. In some
embodiments, flow cytometry sequentially or simultaneously measures
multiple cell characteristics. In some instances, cytometry may
occur within one or more of the tips/vessels described herein.
Cytometry may be combined with cell sorting, where detection of
cells that fulfill a specific set of characteristics are diverted
from the flow stream and collected for storage, additional
analysis, and/or processing. Such sorting may separate multiple
populations of cells based on different sets of characteristics,
such as 3 or 4-way sorting.
FIG. 7 shows a system 700 having a plurality of modules 701-706 and
a cytometry station 707, in accordance with an embodiment of the
invention. The plurality of modules include a first module 701,
second module 702, third module 703, fourth module 704, fifth
module 705 and sixth module 706.
The cytometry station 707 is operatively coupled to each of the
plurality of modules 701-706 by way of a sample handling system
708. The sample handling system 708 may include a pipette, such as
a positive displacement, air displacement or suction-type pipette,
as described herein.
The cytometry station 707 includes a cytometer for performing
cytometry on a sample, as described above and in other embodiments
of the invention. The cytometry station 707 may perform cytometry
on a sample while one or more of the modules 701-706 perform other
preparation and/or assaying procedure on another sample. In some
situations, the cytometry station 707 performs cytometry on a
sample after the sample has undergone sample preparation in one or
more of the modules 701-706.
The system 700 includes a support structure 709 having a plurality
of bays (or mounting stations). The plurality of bays is for
docking the modules 701-706 to the support structure 709. The
support structure 709, as illustrated, is a rack.
Each module is secured to rack 709 with the aid of an attachment
member. In an embodiment, an attachment member is a hook fastened
to either the module or the bay. In such a case, the hook is
configured to slide into a receptacle of either the module or the
bay. In another embodiment, an attachment member includes a
fastener, such as a screw fastener. In another embodiment, an
attachment member is formed of a magnetic material. In such a case,
the module and bay may include magnetic materials of opposite
polarities so as to provide an attractive force to secure the
module to the bay. In another embodiment, the attachment member
includes one or more tracks or rails in the bay. In such a case, a
module includes one or more structures for mating with the one or
more tracks or rails, thereby securing the module to the rack 709.
Optionally, power may be provided by the rails.
An example of a structure that may permit a module to mate with a
rack may include one or more pins. In some cases, modules receive
power directly from the rack. In some cases, a module may be a
power source like a lithion ion, or fuel cell powered battery that
powers the device internally. In an example, the modules are
configured to mate with the rack with the aid of rails, and power
for the modules comes directly from the rails. In another example,
the modules mate with the rack with the aid of attachment members
(rails, pins, hooks, fasteners), but power is provided to the
modules wirelessly, such as inductively (i.e., inductive
coupling).
In some embodiments, a module mating with a rack need not require
pins. For example, an inductive electrical communication may be
provided between the module and rack or other support. In some
instances, wireless communications may be used, such as with the
aid of ZigBee communications or other communication protocols.
Each module may be removable from the rack 709. In some situations,
one module is replaceable with a like, similar or different module.
In an embodiment, a module is removed from the rack 709 by sliding
the module out of the rack. In another embodiment, a module is
removed from the rack 709 by twisting or turning the module such
that an attachment member of the module disengages from the rack
709. Removing a module from the rack 709 may terminate any
electrical connectivity between the module and the rack 709.
In an embodiment, a module is attached to the rack by sliding the
module into the bay. In another embodiment, a module is attached to
the rack by twisting or turning the module such that an attachment
member of the module engages the rack 709. Attaching a module to
the rack 709 may establish an electrical connection between the
module and the rack. The electrical connection may be for providing
power to the module or to the rack or to the device from the module
and/or providing a communications bus between the module and one or
more other modules or a controller of the system 700.
Each bay of the rack may be occupied or unoccupied. As illustrated,
all bays of the rack 709 are occupied with a module. In some
situations, however, one or more of the bays of the rack 709 are
not occupied by a module. In an example, the first module 701 has
been removed from the rack. The system 700 in such a case may
operate without the removed module.
In some situations, a bay may be configured to accept a subset of
the types of modules the system 700 is configured to use. For
example, a bay may be configured to accept a module capable of
running an agglutination assay but not a cytometry assay. In such a
case, the module may be "specialized" for agglutination.
Agglutination may be measured in a variety of ways. Measuring the
time-dependent change in turbidity of the sample is one method. One
can achieve this by illuminating the sample with light and
measuring the reflected light at 90 degrees with an optical sensor,
such as a photodiode or camera. Over time, the measured light would
increase as more light is scattered by the sample. Measuring the
time dependent change in transmittance is another example. In the
latter case, this can be achieved by illuminating the sample in a
vessel and measuring the light that passes through the sample with
an optical sensor, such as a photodiode or a camera. Over time, as
the sample agglutinates, the measured light may reduce or increase
(depending, for example, on whether the agglutinated material
remains in suspension or settles out of suspension). In other
situations, a bay may be configured to accept all types of modules
that the system 700 is configured to use, ranging from detection
stations to the supporting electrical systems.
Each of the modules may be configured to function (or perform)
independently from the other modules. In an example, the first
module 701 is configured to perform independently from the second
702, third 703, fourth 704, fifth 705 and sixth 706 modules. In
other situations, a module is configured to perform with one or
more other modules. In such a case, the modules may enable parallel
processing of one or more samples. In an example, while the first
module 701 prepares a sample, the second module 702 assays the same
or different sample. This may enable a minimization or elimination
of downtime among the modules.
The support structure (or rack) 709 may have a server type
configuration. In some situations, various dimensions of the rack
are standardized. In an example, spacing between the modules
701-706 is standardized as multiples of at least about 0.5 inches,
or 1 inch, or 2 inches, or 3 inches, or 4 inches, or 5 inches, or 6
inches, or 7 inches, or 8 inches, or 9 inches, or 10 inches, or 11
inches, or 12 inches.
The rack 709 may support the weight of one or more of the modules
701-706. Additionally, the rack 709 has a center of gravity that is
selected such that the module 701 (top) is mounted on the rack 709
without generating a moment arm that may cause the rack 709 to spin
or fall over. In some situations, the center of gravity of the rack
709 is disposed between the vertical midpoint of the rack and a
base of the rack, the vertical midpoint being 50% from the base of
the rack 709 and a top of the rack. In an embodiment, the center of
gravity of the rack 709, as measured along a vertical axis away
from the base of the rack 709, is disposed at least about 0.1%, or
1%, or 10%, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%,
or 90%, or 100% of the height of the rack as measured from the base
of the rack 709.
A rack may have multiple bays (or mounting stations) configured to
accept one or more modules. In an example, the rack 709 has six
mounting stations for permitting each of the modules 701-706 to
mount the rack. In some situations, the bays are on the same side
of the rack. In other situations, the bays are on alternating sides
of the rack.
In some embodiments, the system 700 includes an electrical
connectivity component for electrically connecting the modules
701-706 to one another. The electrical connectivity component may
be a bus, such as a system bus. In some situations, the electrical
connectivity component also enables the modules 701-706 to
communicate with each other and/or a controller of the system
700.
In some embodiments, the system 700 includes a controller (not
shown) for facilitating processing of samples with the aid of one
or more of the modules 701-706. In an embodiment, the controller
facilitates parallel processing of the samples in the modules
701-706. In an example, the controller directs the sample handling
system 708 to provide a sample in the first module 701 and second
module 702 to run different assays on the sample at the same time.
In another example, the controller directs the sample handling
system 708 to provide a sample in one of the modules 701-706 and
also provide the sample (such as a portion of a finite volume of
the sample) to the cytometry station 707 so that cytometry and one
or more other sample preparation procedures and/or assays are done
on the sample in parallel. In such fashion, the system minimizes,
if not eliminates, downtime among the modules 701-706 and the
cytometry station 707.
Each individual module of the plurality of modules may include a
sample handling system for providing samples to and removing
samples from various processing and assaying modules of the
individual module. In addition, each module may include various
sample processing and/or assaying modules, in addition to other
components for facilitating processing and/or assaying of a sample
with the aid of the module. The sample handling system of each
module may be separate from the sample handling system 708 of the
system 700. That is, the sample handling system 708 transfers
samples to and from the modules 701-706, whereas the sample
handling system of each module transfers samples to and from
various sample processing and/or assaying modules included within
each module.
In the illustrated example of FIG. 7, the sixth module 706 includes
a sample handling system 710 including a suction-type pipette 711
and positive displacement pipette 712. The sixth module 706
includes a centrifuge 713, a spectrophotometer 714, a nucleic acid
assay (such as a polymerase chain reaction (PCR) assay) station 715
and PMT 716. An example of the spectrophotometer 714 is shown in
FIG. 27 (see below). The sixth module 706 further includes a
cartridge 717 for holding a plurality of tips for facilitating
sample transfer to and from each processing or assaying module of
the sixth module.
In an embodiment, the suction type pipette 711 includes 1 or more,
or 2 or more, or 3 or more, or 4 or more, or 5 or more, or 6 or
more, or 7 or more, or 8 or more, or 9 or more, or 10 or more, or
15 or more, or 20 or more, or 30 or more, or 40 or more, or 50 or
more heads. In an example, the suction type pipette 711 is an
8-head pipette with eight heads. The suction type pipette 711 may
be as described in other embodiments of the invention.
In some embodiments, the positive displacement pipette 712 has a
coefficient of variation less than or equal to about 20%, 15%, 12%,
10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.3%, or 0.1% or
less. The coefficient of variation is determined according to
.sigma./.mu., wherein `.sigma.` is the standard deviation and
`.mu.` is the mean across sample measurements.
In an embodiment, all modules are identical to one another. In
another embodiment, at least some of the modules are different from
one another. In an example, the first, second, third, fourth,
fifth, and sixth modules 701-706 include a positive displacement
pipette and suction-type pipette and various assays, such as a
nucleic acid assay and spectrophotometer. In another example, at
least one of the modules 701-706 may have assays and/or sample
preparation stations that are different from the other modules. In
an example, the first module 701 includes an agglutination assay
but not a nucleic acid amplification assay, and the second module
702 includes a nucleic acid assay but not an agglutination assay.
Modules may not include any assays.
In the illustrated example of FIG. 7, the modules 701-706 include
the same assays and sample preparation (or manipulation) stations.
However, in other embodiments, each module includes any number and
combination of assays and processing stations described herein.
The modules may be stacked vertically or horizontally with respect
to one another. Two modules are oriented vertically in relation to
one another if they are oriented along a plane that is parallel,
substantially parallel, or nearly parallel to the gravitational
acceleration vector. Two modules are oriented horizontally in
relation to one another if they are oriented along a plane
orthogonal, substantially orthogonal, or nearly orthogonal to the
gravitational acceleration vector.
In an embodiment, the modules are stacked vertically, i.e., one
module on top of another module. In the illustrated example of FIG.
7, the rack 709 is oriented such that the modules 701-706 are
disposed vertically in relation to one another. However, in other
situations the modules are disposed horizontally in relation to one
another. In such a case, the rack 709 may be oriented such that the
modules 701-706 may be situated horizontally alongside one
another.
Referring now to FIG. 7A, yet another embodiment of a system 730 is
shown with a plurality of modules 701 to 704. This embodiment of
FIG. 7A shows a horizontal configuration wherein the modules 701 to
704 are mounted to a support structure 732 on which a transport
device 734 can move along the X, Y, and/or optionally Z axis to
move elements such as but not limited sample vessels, tips,
cuvettes, or the like within a module and/or between modules. By
way of non-limiting example, the modules 701-704 are oriented
horizontally in relation to one another if they are oriented along
a plane orthogonal, substantially orthogonal, or nearly orthogonal
to the gravitational acceleration vector.
It should be understood that, like the embodiment of FIG. 7,
modules 701-704 may all be modules that are identical to one
another. In another embodiment, at least some of the modules are
different from one another. In an example, the first, second,
third, and/or fourth modules 701-704 may be replaced by one or more
other modules that can occupy the location of the module being
replaced. The other modules may optionally provide different
functionality such as but not limited to a replacing one of the
modules 701-704 with one or more cytometry modules 707,
communications modules, storage modules, sample preparation
modules, slide preparation modules, tissue preparation modules, or
the like. For example, one of the modules 701-704 may be replaced
with one or more modules that provide a different hardware
configuration such as but not limited to provide a thermal
controlled storage chamber for incubation, storage between testing,
and/or storage after testing. Optionally, the module replacing one
or more of the modules 701-704 can provide a non-assay related
functionality, such as but not limited to additional
telecommunication equipment for the system 730, additional imaging
or user interface equipment, or additional power source such as but
not limited to batteries, fuel cells, or the like. Optionally, the
module replacing one or more of the modules 701-704 may provide
storage for additional disposables and/or reagents or fluids. It
should be understood that although FIG. 7A shows only four modules
mounted on the support structure, other embodiments having fewer or
more modules are not excluded from this horizontal mounting
configuration. It should also be understood that configurations may
also be run with not every bay or slot occupied by a module,
particularly in any scenario wherein one or more types of modules
draw more power that other modules. In such a configuration, power
otherwise directed to an empty bay can be used by the module that
may draw more power than the others.
In one non-limiting example, each module is secured to the support
structure 732 with the aid of an attachment member. In an
embodiment, an attachment member is a hook fastened to either the
module or the bay. In such a case, the hook is configured to slide
into a receptacle of either the module or the bay. In another
embodiment, an attachment member includes a fastener, such as a
screw fastener. In another embodiment, an attachment member is
formed of a magnetic material. In such a case, the module and bay
may include magnetic materials of opposite polarities so as to
provide an attractive force to secure the module to the bay. In
another embodiment, the attachment member includes one or more
tracks or rails in the bay. In such a case, a module includes one
or more structures for mating with the one or more tracks or rails,
thereby securing the module to the support structure 732.
Optionally, power may be provided by the rails.
An example of a structure that may permit a module to mate with a
support structure 732 may include one or more pins. In some cases,
modules receive power directly from the support structure 732. In
some cases, a module may be a power source like a lithium ion, or
fuel cell powered battery that powers the device internally. In an
example, the modules are configured to mate with the support
structure 732 with the aid of rails, and power for the modules
comes directly from the rails. In another example, the modules mate
with the support structure 732 with the aid of attachment members
(rails, pins, hooks, fasteners), but power is provided to the
modules wirelessly, such as inductively (i.e., inductive
coupling).
Referring now to FIG. 7B, yet another embodiment of a system 740 is
shown with a plurality of modules 701 to 706. FIG. 7B shows that a
support structure 742 is provided that can allow a transport device
744 to move along the X, Y, and/or optionally Z axis to transport
elements such as but not limited sample vessels, tips, cuvettes, or
the like within a module and/or between modules. The transport
device 744 can be configured to access either column of modules.
Optionally, some embodiments may have more than one transport
device 744 to provide higher throughput of transport capabilities
for vessels or other elements between modules. For clarity, the
transport device 744 shown in phantom may represent a second
transport device 744. Alternatively, it can also be used to show
where the transport device 744 is located when service the second
column of modules. It should also be understood that embodiments
having still further rows and/or columns can also be created by
using a larger support structure to accommodate such a
configuration.
It should be understood that, like the embodiment of FIG. 7,
modules 701-706 may all be modules that are identical to one
another. In another embodiment, at least some of the modules are
different from one another. In an example, the first, second,
third, and/or fourth modules 701-706 may be replaced by one or more
other modules that can occupy the location of the module being
replaced. The other modules may optionally provide different
functionality such as but not limited to a replacing one of the
modules 701-706 with one or more cytometry modules 707,
communications modules, storage modules, sample preparation
modules, slide preparation modules, tissue preparation modules, or
the like.
It should be understood that although FIG. 7B shows only six
modules mounted on the support structure, other embodiments having
fewer or more modules are not excluded from this horizontal and
vertical mounting configuration. It should also be understood that
configurations may also be run with not every bay or slot occupied
by a module, particularly in any scenario wherein one or more types
of modules draw more power that other modules. In such a
configuration, power otherwise directed to an empty bay can be used
by the module that may draw more power than the others.
Referring now to FIG. 7C, yet another embodiment of a system 750 is
shown with a plurality of modules 701, 702, 703, 704, 706, and 707.
FIG. 7C also shows that they system 750 has an additional module
752 that can with one or more modules that provide a different
hardware configuration such as but not limited to provide a thermal
controlled storage chamber for incubation, storage between testing,
or storage after testing. Optionally, the module replacing one or
more of the modules 701-704 can provide a non-assay related
functionality, such as but not limited to additional
telecommunication equipment for the system 730, additional imaging
or user interface equipment, or additional power source such as but
not limited to batteries, fuel cells, or the like. Optionally, the
module replacing one or more of the modules 701-707 may provide
storage for additional disposables and/or reagents or fluids.
It should be understood that although FIG. 7C shows seven modules
mounted on the support structure, other embodiments having fewer or
more modules are not excluded from this mounting configuration. It
should also be understood that configurations may also be run with
not every bay or slot occupied by a module, particularly in any
scenario wherein one or more types of modules draw more power that
other modules. In such a configuration, power otherwise directed to
an empty bay can be used by the module that may draw more power
than the others.
In some embodiments, the modules 701-706 are in communication with
one another and/or a controller of the system 700 by way of a
communications bus ("bus"), which may include electronic circuitry
and components for facilitating communication among the modules
and/or the controller. The communications bus includes a subsystem
that transfers data between the modules and/or controller of the
system 700. A bus may bring various components of the system 700 in
communication with a central processing unit (CPU), memory (e.g.,
internal memory, system cache) and storage location (e.g., hard
disk) of the system 700.
A communications bus may include parallel electrical wires with
multiple connections, or any physical arrangement that provides
logical functionality as a parallel electrical bus. A
communications bus may include both parallel and bit-serial
connections, and can be wired in either a multidrop (i.e.,
electrical parallel) or daisy chain topology, or connected by
switched hubs. In an embodiment, a communications bus may be a
first generation bus, second generation bus or third generation
bus. The communications bus permits communication between each of
the modules and other modules and/or the controller. In some
situations, the communications bus enables communication among a
plurality of systems, such as a plurality of systems similar or
identical to the system 700.
The system 700 may include one or more of a serial bus, parallel
bus, or self-repairable bus. A bus may include a master scheduler
that control data traffic, such as traffic to and from modules
(e.g., modules 701-706), controller, and/or other systems. A bus
may include an external bus, which connects external devices and
systems to a main system board (e.g., motherboard), and an internal
bus, which connects internal components of a system to the system
board. An internal bus connects internal components to one or more
central processing units (CPUs) and internal memory.
In some embodiments, the communication bus may be a wireless bus.
The commuincations bus may be a Firewire (IEEE 1394), USB (1.0,
2.0, 3.0, or others), or Thunderbolt.
In some embodiments, the system 700 includes one or more buses
selected from the group consisting of Media Bus, Computer Automated
Measurement and Control (CAMAC) bus, industry standard architecture
(ISA) bus, USB bus, Firewire, Thunderbolt, extended ISA (EISA) bus,
low pin count bus, MBus, MicroChannel bus, Multibus, NuBus or IEEE
1196, OPTi local bus, peripheral component interconnect (PCI) bus,
Parallel Advanced Technology Attachment (ATA) bus, Q-Bus, S-100 bus
(or IEEE 696), SBus (or IEEE 1496), SS-50 bus, STEbus, STD bus (for
STD-80 [8-bit] and STD32 [16-/32-bit]), Unibus, VESA local bus,
VMEbus, PC/104 bus, PC/104 Plus bus, PC/104 Express bus, PCI-104
bus, PCIe-104 bus, 1-Wire bus, HyperTransport bus, Inter-Integrated
Circuit (I.sup.2C) bus, PCI Express (or PCIe) bus, Serial ATA
(SATA) bus, Serial Peripheral Interface bus, UNI/O bus, SMBus,
2-wire or 3-wire interface, self-repairable elastic interface buses
and variants and/or combinations thereof.
In some situations, the system 700 includes a Serial Peripheral
Interface (SPI), which is an interface between one or more
microprocessors and peripheral elements or I/O components (e.g.,
modules 701-706) of the system 700. The SPI can be used to attach 2
or more, or 3 or more, or 4 or more, or 5 or more, or 6 or more, or
7 or more, or 8 or more, or 9 or more, or 10 or more or 50 or more
or 100 or more SPI compatible I/O components to a microprocessor or
a plurality of microprocessors. In other instances, the system 700
includes RS-485 or other standards.
In an embodiment, an SPI is provided having an SPI bridge having a
parallel and/or series topology. Such a bridge allows selection of
one of many SPI components on an SPI I/O bus without the
proliferation of chip selects. This is accomplished by the
application of appropriate control signals, described below, to
allow daisy chaining the device or chip selects for the devices on
the SPI bus. It does however retain parallel data paths so that
there is no Daisy Chaining of data to be transferred between SPI
components and a microprocessor.
In some embodiments, an SPI bridge component is provided between a
microprocessor and a plurality of SPI I/O components which are
connected in a parallel and/or series (or serial) topology. The SPI
bridge component enables parallel SPI using MISO and MOSI lines and
serial (daisy chain) local chip select connection to other slaves
(CSL/). In an embodiment, SPI bridge components provided herein
resolve any issues associated with multiple chip selects for
multiple slaves. In another embodiment, SPI bridge components
provided herein support four, eight, sixteen, thirty two, sixty
four or more individual chip selects for four SPI enabled devices
(CS1/-CS4/). In another embodiment, SPI bridge components provided
herein enable four times cascading with external address line
setting (ADR0-ADR1). In some situations, SPI bridge components
provided herein provide the ability to control up to eight,
sixteen, thirty two, sixty four or more general output bits for
control or data. SPI bridge components provided herein in some
cases enable the control of up to eight, sixteen, thirty two, sixty
four or more general input bits for control or data, and may be
used for device identification to the master and/or diagnostics
communication to the master.
FIG. 8 shows an example of a multi-rack system. For example, a
first rack 800a may be connected and/or adjacent to a second rack
800b. Each rack may include one or more module 810. In another
embodiment, the system includes a plurality of racks that are
disposed vertically in relation to one another--that is, one rack
on top of another rack. In some embodiments, the racks may form a
vertical array (e.g., one or more racks high and one or more racks
wide), a horizontal array (one or more racks wide, one or more
racks long), or a three-dimensional array (one or more racks high,
one or more racks wide, and one or more racks long).
In some embodiments, the modules may be disposed on the racks,
depending on rack configuration. For example, if vertically
oriented racks are placed adjacent to one another, modules may be
disposed vertically along the racks. If horizontally oriented racks
are placed on top of one another, modules may be disposed
horizontally along the racks. Racks may be connected to one another
via any sort of connecting interface, including those previously
described for modules. Racks may or may not contact one another.
Racks may be mechanically and/or electrically connected to one
another.
In another embodiment, the system includes a plurality of racks,
and each rack among the plurality of racks is configured for a
different use, such as sample processing. In an example, a first
rack is configured for sample preparation and cytometry and a
second rack is configured for sample preparation and agglutination.
In another embodiment, the racks are disposed horizontally (i.e.,
along an axis orthogonal to the gravitational acceleration vector).
In another embodiment, the system includes a plurality of racks,
and two or more racks among the plurality of racks are configured
for the same use, such as sample preparation or processing.
In some cases, a system having a plurality of racks includes a
single controller that is configured to direct (or facilitate)
sample processing in each rack. In other cases, each individual
rack among a plurality of racks includes a controller configured to
facilitate sample processing in the individual rack. The
controllers may be in network or electrical communication with one
another.
A system having a plurality of racks may include a communications
bus (or interface) for bringing the plurality of racks in
communication with one another. This permits parallel processing
among the racks. For instance, for a system including two racks
commutatively coupled to one another with the aid of a
communications bus, the system processes a first sample in a first
of the two racks while the system processes a second sample in a
second of the two racks.
A system having a plurality of racks may include one or more sample
handling systems for transferring samples to and from racks. In an
example, a system includes three racks and two sample handling
systems to transfer samples to and from each of the first, second
and third racks.
In some embodiments, sample handling systems are robots or
robotic-arms for facilitating sample transfer among racks, among
modules in a rack, and/or within modules. In some embodiments, each
module may have one or more robots. The robots may be useful for
moving components within or amongst different modules or other
components of a system. In other embodiments, sample handling
systems are actuator (e.g., electrical motors, pneumatic actuators,
hydraulic actuators, linear actuators, comb drive, piezoelectric
actuators and amplified piezoelectric actuators, thermal bimorphs,
micromirror devices and electroactive polymers) devices for
facilitating sample transfer among racks or modules in a rack. In
other embodiments, sample handling systems include pipettes, such
as positive displacement, suction-type or air displacement pipettes
which may optionally have robotic capabilities or robots with
pipetting capability. One or more robots may be useful for
transferring sampling systems from one location to another.
The robotic arm (also "arm" here) is configured to transfer (or
shuttle) samples to and from modules or, in some cases, among
racks. In an example, an arm transfers samples among a plurality of
vertically oriented modules in a rack. In another example, an arm
transfers samples among a plurality of horizontally oriented
modules in a rack. In another example, an arm transfers samples
among a plurality of horizontally and vertically oriented modules
in a rack.
Each arm may include a sample manipulation device (or member) for
supporting a sample during transport to and from a module and/or
one or more other racks. In an embodiment, the sample manipulation
device is configured to support a tip or vessel (e.g., container,
vial) having the sample. The sample manipulation device may be
configured to support a sample support, such as a microcard or a
cartridge. Alternatively, the manipulation device may have one or
more features that may permit the manipulation device to serve as a
sample support. The sample manipulation device may or may not
include a platform, gripper, magnet, fastener, or any other
mechanism that may be useful for the transport.
In some embodiments, the arm is configured to transfer a module
from one bay to another. In an example, the arm transfers a module
from a first bay in a first rack to a first bay in a second rack,
or from the first bay in the first rack to a second bay in the
second rack.
The arm may have one or more actuation mechanism that may permit
the arm to transfer the sample and/or module. For example, one or
more motor may be provided that may permit movement of the arm.
In some instances, the arm may move along a track. For example, a
vertical and/or horizontal track may be provided. In some
instances, the robot arm may be a magnetic mount with a kinematic
locking mount.
In some embodiments, robots, such as a robotic arm, may be provided
within a device housing. The robots may be provided within a rack,
and/or within a module. Alternatively, they may be external to a
rack and/or module. They may permit movement of components within a
device, between tracks, between modules, or within modules. The
robots may move one or more component, including but not limited to
a sample handling system, such as a pipette, vessel/tip, cartridge,
centrifuge, cytometer, camera, detection unit, thermal control
unit, assay station or system, or any other component described
elsewhere herein. The components may be movable within a module,
within a rack, or within the device. The components may be movable
within the device even if no rack or module is provided within the
device. The robots may move one or more module. The modules may be
movable within the device. The robots may move one or more racks.
The racks may be movable within the device.
The robots may move using one or more different actuation
mechanism. Such actuation mechanisms may use mechanical components,
electromagnetic, magnetism, thermal properties, piezoelectric
properties, optics, or any other properties or combinations
thereof. For example, the actuation mechanisms may use a motor
(e.g., linear motor, stepper motor), lead screw, magnetic track, or
any other actuation mechanism. In some instances, the robots may be
electronically, magnetically, thermally or optically
controlled.
FIG. 25A provides an example of a magnetic way of controlling the
position of a robot or other item. A top view shows an array of
magnets 6800. A coil support structure 6810 may be provided
adjacent to the magnets. A coil support structure may be made from
electrically conductive, weak magnetic material.
The array of magnets may include a strip of magnets, or an
m.times.n array of magnets, where m and/or n is greater than or
equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 25, 30, 40, 50, or 100.
FIG. 25B provides a side view of the magnetic control. A coil
support structure 6810 may have one, two, three, four, five, six,
seven, eight or more conducting coils 6820 thereon. The coil
support structure may be adjacent to an array of magnets 6800.
Passive damping may be provided as well as use of electrically
conductive magnetic materials.
The actuation mechanisms may be capable of moving with very high
precision. For example, the robots may be capable of moving with a
precision of within about 0.01 nm, 0.05 nm, 0.1 nm, 0.5 nm, 1 nm, 5
nm, 10 nm, 30 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300
nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, 1 .mu.m, 1.5
.mu.m, 2 .mu.m, 3 .mu.m, 4 .mu.m, 5 .mu.m, 7 .mu.m, 10 .mu.m, 15
.mu.m, 20 .mu.m, 25 .mu.m, 30 .mu.m, 40 .mu.m, 50 .mu.m, 75 .mu.m,
100 .mu.m, 150 .mu.m, 200 .mu.m, 250 .mu.m, 300 .mu.m, 500 .mu.m,
750 .mu.m, 1 mm, 2 mm, or 3 mm.
The robots may be capable of moving in any direction. The robots
may be capable of moving in a lateral direction (e.g., horizontal
direction) and/or a vertical direction. A robot may be capable of
moving within a horizontal plane, and/or a vertical plane. A robot
may be capable of moving in an x, y, and/or z direction wherein an
x-axis, y-axis, and z-axis are orthogonal to one another. Some
robots may only move within one dimension, two dimensions, and/or
three dimensions.
In some situations, the term "system" as used herein may refer to a
"device" or "sample processing device" disclosed herein, unless the
context clearly dictates otherwise.
Plug-and-Play
In an aspect of the invention, plug-and-play systems are described.
The plug-and-play systems are configured to assay at least one
sample, such as a tissue or fluid sample, from a subject.
In some embodiments, the plug-and-play system comprises a
supporting structure having a mounting station configured to
support a module among a plurality of modules. The module is
detachable from the mounting station. In some cases, the module is
removably detachable--that is, the module may be removed from the
mounting station and returned to its original position on the
mounting station. Alternatively, the module may be replaced with
another module.
In an embodiment, the module is configured to perform without the
aid of another module in the system (a) at least one sample
preparation procedure selected from the group consisting of sample
processing, centrifugation, magnetic separation, or (b) at least
one type of assay selected from the group consisting of
immunoassay, nucleic acid assay, receptor-based assay, cytometric
assay, colorimetric assay, enzymatic assay, electrophoretic assay,
electrochemical assay, spectroscopic assay, chromatographic assay,
microscopic assay, topographic assay, calorimetric assay,
turbidimetric assay, agglutination assay, radioisotope assay,
viscometric assay, coagulation assay, clotting time assay, protein
synthesis assay, histological assay, culture assay, osmolarity
assay, and/or other types of assays or combinations thereof.
In an embodiment, the module is configured to be in electrical,
electro-magnetic or optoelectronic communication with a controller.
The controller is configured to provide one or more instructions to
the module or individual modules of the plurality of modules to
facilitate performance of the at least one sample preparation
procedure or the at least one type of assay.
In an embodiment, the system is in communication with a controller
for coordinating or facilitating the processing of samples. In an
embodiment, the controller is part of the system. In another
embodiment, the controller is remotely located with respect to the
system. In an example, the controller is in network communication
with the system.
In an embodiment, a module is coupled to a support structure. The
support structure may be a rack having a plurality of bays for
accepting a plurality of modules. The support structure is part of
the system configured to accept the module. In an embodiment, the
module is hot-swappable--that is, the module may be exchanged with
another module or removed from the support structure while the
system is processing other samples.
In some embodiments, upon a user hot-swapping a first module for a
second module, the system is able to detect and identify the second
module and update a list of modules available for use by the
system. This permits the system to determine which resources are
available for use by the system for processing a sample. For
instance, if a cytometry module is swapped for an agglutination
module and the system has no other cytometry modules, then the
system will know that the system is unable to perform cytometry on
a sample.
The plurality of modules may include the same module or different
modules. In some cases, the plurality of modules are multi-purpose
(or multi-use) modules configured for various preparation and/or
processing functionalities. In other cases, the plurality of
modules may be special-use (or special-purpose) modules configured
for fewer functionalities than the multi-purpose modules. In an
example, one or more of the modules is a special-use module
configured for cytometry.
In some embodiments, the system is configured to detect the type of
module without the need for any user input. Such plug-and-play
functionality advantageously enables a user to insert a module into
the system for use without having to input any commands or
instructions.
In some situations, the controller is configured to detect a
module. In such a case, when a user plugs a module into the system,
the system detects the module and determines whether the module is
a multi-use module or special-use module. In some cases, the system
is able to detect a module with the use of an electronic
identifier, which may include a unique identifier. In other cases,
the system is able to detect the module with the aid of a physical
identifier, such as a bar code or an electronic component
configured to provide a unique radio frequency identification
(RFID) code, such as an RFID number or a unique ID through the
system bus.
The system may detect a module automatically or upon request from a
user or another system or electronic component in communication
with the system. In an example, upon a user inputting the module
701 into the system 700, the system 700 detects the module, which
may permit the system 700 to determine the type of module (e.g.,
cytometry module).
In some situations, the system is configured to also determine the
location of the module, which may permit the system to build a
virtual map of modules, such as, e.g., for facilitating parallel
processing (see below). In an example, the system 700 is configured
to detect the physical location of each of the modules 701-706. In
such a case, the system 700 knows that the first module 701 is
located in a first port (or bay) of the system 700.
Modules may have the same component or different components. In an
embodiment, each module has the same components, such as those
described above in the context of FIG. 7. That is, each module
includes pipettes and various sample processing stations. In
another embodiment, the modules have different components. In an
example, some modules are configured for cytometry assays while
other are configured for agglutination assays.
In another embodiment, a shared module may be a dedicated cooling
or heating unit that is providing cooling or heating capabilities
to the device or other modules as needed.
In another embodiment, a shared resource module may be a
rechargeable battery pack. Examples of batteries may include, but
are not limited to, zinc-carbon, zinc-chloride, alkaline,
oxy-nickel hydroxide, lithium, mercury oxide, zinc-air, silver
oxide, NiCd, lead acid, NiMH, NiZn, or lithium ion. These batteries
may be hot-swappable or not. The rechargeable battery may be
coupled with external power source. The rechargeable battery module
may be recharged while the device is plugged into an external power
source or the battery module may be taken out of device and
recharged externally to the device in a dedicated recharging
station or directly plugged into an external power supply. The
dedicated recharging station may be the device or be operatively
connected to the device (e.g., recharging can be done via induction
without direct physical contact). The recharging station may be a
solar powered recharging station or may be powered by other clean
or conventional sources. The recharging station may be powered by a
conventional power generator. The battery module may provide
Uninterrupted Power Supply (UPS) to the device or bank of devices
in case of power interruptions from external supply.
In another embodiment, the shared resource module may be a `compute
farm` or collection of high performance general purpose or specific
purpose processors packed together with appropriate cooling as a
module dedicated to high performance computing inside the device or
to be shared by collection of devices.
In another embodiment, a module may be an assembly of high
performance and/or high capacity storage devices to provide large
volume of storage space (e.g. 1 TB, 2 TB, 10 TB, 100 TB, 1 PB, 100
PB or more) on the device to be shared by all modules, modules in
other devices that may be sharing resources with the device and
even by the external controller to cache large amounts of data
locally to a device or a physical site or collection of sites or
any other grouping of devices.
In another embodiment, a shared module may be a satellite
communication module that is capable of providing communication
capabilities to communicate with satellite from the device or other
devices that may be sharing resources.
In another embodiment, the module may be an internet router and/or
a wireless router providing full routing and/or a hotspot
capability to the device or bank of devices that are allowed to
share the resources of the device.
In some embodiments, the module, alone or in combination with other
modules (or systems) provided herein, may act as a `data center`
for either the device or bank of devices allowed to share the
resources of the device providing high performance computing, high
volume storage, high performance networking, satellite or other
forms of dedicated communication capabilities in the device for a
given location or site or for multiple locations or sites.
In one embodiment, a shared module may be a recharging station for
wireless or wired peripherals that are used in conjunction with the
device.
In one embodiment, a shared module may be a small refrigeration or
temperature control storage unit to stores, samples, cartridges,
other supplies for the device.
In another embodiment, a module may be configured to automatically
dispense prescription or other pharmaceutical drugs. The module may
also have other components such as packet sealers and label
printers that make packaging and dispensing drugs safe and
effective. The module may be programmed remotely or in the device
to automatically dispense drugs based on real time diagnosis of
biological sample, or any other algorithm or method that determines
such need. The system may have the analytics for pharmacy decision
support to support the module around treatment decisions, dosing,
and other pharmacy-related decision support.
Modules may have swappable components. In an example, a module has
a positive displacement pipette that is swappable with the same
type of pipette or a different type of pipette, such as a
suction-type pipette. In another example, a module has an assay
station that is swappable with the same type of assay station
(e.g., cytometry) or a different type of assay station (e.g.,
agglutination). The module and system are configured to recognize
the modules and components in the modules and update or modify
processing routines, such as parallel processing routines, in view
of the modules coupled to the system and the components in each of
the modules.
In some cases, the modules may be external to the device and
connected to the device through device's bus (e.g. via a USB
port).
FIG. 9 shows an example of a module 900 having one or more
components 910. A module may have one or more controller. The
components 910 are electrically coupled to one another and/or the
controller via a communications bus ("Bus"), such as, for example,
a bus as described above in the context of FIG. 7. In an example,
the module 900 includes a one or more buses selected from the group
consisting of Media Bus, Computer Automated Measurement and Control
(CAMAC) bus, industry standard architecture (ISA) bus, extended ISA
(EISA) bus, low pin count bus, MBus, MicroChannel bus, Multibus,
NuBus or IEEE 1196, OPTi local bus, peripheral component
interconnect (PCI) bus, Parallel Advanced Technology Attachment
(ATA) bus, Q-Bus, S-100 bus (or IEEE 696), SBus (or IEEE 1496),
SS-50 bus, STEbus, STD bus (for STD-80 [8-bit] and STD32
[16-/32-bit]), Unibus, VESA local bus, VMEbus, PC/104 bus, PC/104
Plus bus, PC/104 Express bus, PCI-104 bus, PCIe-104 bus, 1-Wire
bus, HyperTransport bus, Inter-Integrated Circuit (I.sup.2C) bus,
PCI Express (or PCIe) bus, Serial ATA (SATA) bus, Serial Peripheral
Interface bus, UNI/O bus, SMBus, self-repairable elastic interface
buses and variants and/or combinations thereof. In an embodiment,
the communications bus is configured to communicatively couple the
components 910 to one another and the controller. In another
embodiment, the communications bus is configured to communicatively
couple the components 910 to the controller. In an embodiment, the
communications bus is configured to communicatively couple the
components 910 to one another. In some embodiments, the module 900
includes a power bus that provides power to one or more of the
components 910. The power bus may be separate from the
communications bus. In other embodiments, power is provided to one
or more of the components with the aid of the communications
bus.
In an embodiment, the components 910 may be swappable, such as
hot-swappable. In another embodiment, the components 910 are
removable from the module 900. The components 910 are configured
for sample preparation, processing and testing. Each of the
components 910 may be configured to process a sample with the aid
of one or more sample processing, preparation and/or testing
routines.
In the illustrated example, the module 900 includes six components
910: a first component (Component 1), second component (Component
2), third component (Component 3), fourth component (Component 4),
fifth component (Component 5), and sixth component (Component 6).
The module 900 generally includes 1 or more, or 2 or more, or 3 or
more, or 4 or more, or 5 or more, or 6 or more, or 7 or more, or 8
or more, or 9 or more, or 10 or more, or 20 or more, or 30 or more,
or 40 or more, or 50 or more, or 100 or more components 910. The
components 910, with the aid of the controller communicative (and
electrically) coupled to the components 910, are configured for
serial and/or parallel processing of a sample.
In an example, Component 1 is a centrifuge, Component 2 is a
spectrophotometer, Component 3 is a Nucleic Acid (assay station and
Component 4 is a PMT station, Component 5 is a tip holder and
Component 6 is a sample washing station.
In an embodiment, the components are configured to process a sample
in series. In such a case, a sample is processed in the components
in sequence (i.e., Component 1, Component 2, etc.). In another
embodiment, sample processing is not necessarily sequential. In an
example, a sample is first processed in Component 4 followed by
Component 1.
In an embodiment, the components 910 process samples in parallel.
That is, a component may process a sample while one or more other
components process the sample or a different sample. In an example,
Component 1 processes a sample while Component 2 processes a
sample. In another embodiment, the components 910 process sample
sequentially. That is, while one component processes a sample,
another component does not process a sample.
In some embodiments, the module 900 includes a sample handling
system configured to transfer a sample to and from the components
910. In an embodiment, the sample handling system is a positive
displacement pipette. In another embodiment, the sample handling
system is a suction-type pipette. In another embodiment, the sample
handling system is an air-displacement pipette. In another
embodiment, the sample handing system includes one or more of a
suction-type pipette, positive displacement pipette and
air-displacement pipette. In another embodiment, the sample handing
system includes any two of a suction-type pipette, positive
displacement pipette and air-displacement pipette. In another
embodiment, the sample handing system includes a suction-type
pipette, positive displacement pipette and air-displacement
pipette.
In some embodiments, the components 910 are swappable with other
components. In an embodiment, each component is swappable with the
same component (i.e., another component having the same
functionality). In another embodiment, each component is swappable
with a different component (i.e., a component having different
functionality). The components 910 are hot swappable or removable
upon shutdown of the module 900.
FIG. 10 shows a system 1000 having a plurality of modules mounted
to bays of the system 1000, in accordance with an embodiment of the
invention. The system includes a first module (Module 1), second
module (Module 2) and third module (Module 3). The system 1000
includes a communications bus ("Bus") for bringing a controller of
the system 1000 in communication with each of the modules. The
communications bus (also "system bus" herein) of the system 1000 is
also configured to bring the modules in communication with one
another. In some situations, the controller of the system 1000 is
optional.
With continued reference to FIG. 10, each module includes a
plurality of stations (or sub-modules), designated by Mxy, wherein
`x` designates the module and `y` designates the station. Each
module optionally includes a controller that is communicatively
coupled to each of the stations via a communications bus (also
"module bus" herein). In some cases, a controller is
communicatively coupled to the system bus through the module
bus.
Module 1 includes a first station (M11), second station (M12),
third station (M13) and controller (C1). Module 2 includes a first
station (M21), second station (M22), third station (M23) and
controller (C2). Module 3 includes a first station (M31) and
controller (C3). The controllers of the modules are communicatively
coupled to each of the stations via a communications bus. The
stations are selected from the group consisting of preparation
stations, assaying stations and detection stations. Preparation
stations are configured for sample preparation; assaying stations
are configured for sample assaying; and detection stations are
configured for analyte detection.
In an embodiment, each module bus is configured to permit a station
to be removed such that the module may function without the removed
station. In an example, M11 may be removed from module 1 while
permitting M12 and M13 to function. In another embodiment, each
station is hot-swappable with another station--that is, one station
may be replaced with another station without removing the module or
shutting down the system 1000.
In some embodiments, the stations are removable from the modules.
In other embodiments, the stations are replaceable by other
stations. In an example, M11 is replaced by M22.
With respect to a particular module, each station may be different
or two or more stations may be the same. In an example, M11 is a
centrifuge and M12 is an agglutination station. As another example,
M22 is a nucleic acid assay station and M23 is an x-ray
photoelectron spectroscopy station.
Two or more of the modules may have the same configuration of
stations or a different configuration. In some situations, a module
may be a specialized module. In the illustrated embodiment of FIG.
10, module 3 has a single station, M31, that is communicatively
coupled to C3.
The system 1000 includes a sample handling system for transferring
samples to and from the modules. The sample handling system
includes a positive displacement pipette, suction-type pipette
and/or air-displacement pipette. The sample handling system is
controlled by the controller of the system 1000. In some
situations, the sample handling system is swappable by another
sample handling system, such as a sample handling system
specialized for certain uses.
With continued reference to FIG. 10, each module includes a sample
handling system for transferring samples to and from the stations.
The sample handling system includes a positive displacement
pipette, suction-type pipette and/or air-displacement pipette. The
sample handling system is controlled by a controller in the module.
Alternatively, the sample handling system is controlled by the
controller of the system 1000.
Parallel Processing and Dynamic Resource Sharing
In another aspect of the invention, methods for processing a sample
are provided. The methods are used to prepare a sample and/or
perform one or more sample assays.
In some embodiments, a method for processing a sample comprises
providing a system having plurality of modules as described herein.
The modules of the system are configured to perform simultaneously
(a) at least one sample preparation procedure selected from the
group consisting of sample processing, centrifugation, magnetic
separation and chemical processing, and/or (b) at least one type of
assay selected from the group consisting of immunoassay, nucleic
acid assay, receptor-based assay, cytometric assay, colorimetric
assay, enzymatic assay, electrophoretic assay, electrochemical
assay, spectroscopic assay, chromatographic assay, microscopic
assay, topographic assay, calorimetric assay, turbidimetric assay,
agglutination assay, radioisotope assay, viscometric assay,
coagulation assay, clotting time assay, protein synthesis assay,
histological assay, culture assay, osmolarity assay, and/or other
types of assays or combinations thereof. Next, the system tests for
the unavailability of resources or the presence of a malfunction of
(a) the at least one sample preparation procedure or (b) the at
least one type of assay. Upon detection of a malfunction within at
least one module, the system uses another module of the system or
another system in communication with the system to perform the at
least one sample preparation procedure or the at least one type of
assay.
In some embodiments, the system 700 of FIG. 7 is configured to
allocate resource sharing to facilitate sample preparation,
processing and testing. In an example, one of the modules 701-706
is configured to perform a first sample preparation procedure while
another of the modules 701-706 is configured to perform a second
sample preparation procedure that is different from the first
sample preparation procedure. This enables the system 700 to
process a first sample in the first module 701 while the system 700
processes a second sample or a portion of the first sample. This
advantageously reduces or eliminates downtime (or dead time) among
modules in cases in which processing routines in modules (or
components within modules) require different periods of time to
reach completion. Even if processing routines reach completion
within the same period of time, in situations in which the periods
do not overlap, parallel processing enables the system to optimize
system resources in cases. This may be applicable in cases in which
a module is put to use after another module or if one module has a
start time that is different from that of another module.
The system 700 includes various devices and apparatuses for
facilitating sample transfer, preparation and testing. The sample
handling system 708 enables the transfer of a sample to and from
each of the modules 701-706. The sample handling system 708 may
enable a sample to be processed in one module while a portion of
the sample or a different sample is transferred to or from another
module.
In some situations, the system 700 is configured to detect each of
the modules 701-706 and determine whether a bay configured to
accept modules is empty or occupied by a module. In an embodiment,
the system 700 is able to determine whether a bay of the system 700
is occupied by a general or multi-purpose module, such as a module
configured to perform a plurality of tests, or a specialized
module, such as a module configured to perform select tests. In
another embodiment, the system 700 is able to determine whether a
bay or module in the bay is defective or malfunctioning. The system
may then use other modules to perform sample processing or
testing.
A "multi-purpose module" is configured for a wide array of uses,
such as sample preparation and processing. A multi-purpose module
may be configured for at least 2, or 3, or 4, or 5, or 6, or 7, or
8, or 9, or 10, or 20, or 30, or 40, or 50 uses. A "special-use
module" is a module that is configured for one or more select uses
or a subset of uses, such as at most 1, or 2, or 3, or 4, or 5, or
6, or 7, or 8, or 9, or 10, or 20, or 30, or 50 uses. Such uses may
include sample preparation, processing and/or testing (e.g.,
assay). A module may be a multi-purpose module or special-use
module.
In some cases, a special-use module may include sample preparation
procedures and/or tests not include in other modules.
Alternatively, a special-use module includes a subset of sample
preparation procedures and/or tests included in other modules.
In the illustrated example of FIG. 7, the module 706 may be a
special-use module. Special uses may include, for example, one or
more assays selected from cytometry, agglutination, microscopy
and/or any other assay described elsewhere herein.
In an example, a module is configured to perform cytometry only.
The module is configured for use by the system 700 to perform
cytometry. The cytometry module may be configured to prepare and/or
process a sample prior to performing cytometry on the sample.
In some embodiments, systems are provided that are configured to
process multiple samples in parallel. The samples may be different
samples or portions of the same sample (e.g., portions of a blood
sample). Parallel processing enables the system to make use of
system resources at times when such resources would otherwise not
be used. In such fashion, the system is configured to minimize or
eliminate dead time between processing routines, such as
preparation and/or assay routines. In an example, the system assays
(e.g., by way of cytometry) a first sample in a first module while
the system centrifuges the same or a different sample in a
different module.
In some situations, the system is configured to process a first
sample in a first component of a first module while the system
processes a second sample in a second component of the first
module. The first sample and second sample may be portions of a
larger quantity of a sample, such as portions of a blood sample, or
different sample, such as a blood sample from a first subject and a
blood sample from a second subject, or a urine sample from the
first subject and a blood sample from the first subject. In an
example, the system assays a first sample in the first module while
the system centrifuges a second sample in the first module.
FIG. 11 shows a plurality of plots illustrating a parallel
processing routine, in accordance with an embodiment of the
invention. Each plot illustrates processing in an individual module
as a function of time (abscissa, or "x axis"). In each module, a
step increase with time corresponds to the start of processing and
a step decrease with time corresponds to the termination (or
completion) of processing. The top plot shows processing in a first
module, the middle plot shows processing in a second module, and
the bottom plot shows processing in a third module. The first,
second and third modules are part of the same system (e.g., system
700 of FIG. 7). Alternatively, the first, second and/or third
modules may be part of separate systems.
In the illustrated example, when the first module processes a first
sample, the second module processes a second sample and the third
module processes a third sample. The first and third modules start
processing at the same time, but processing times are different.
This may be the case if, for example, the first module processes a
sample with the aid of an assay or preparation routine that is
different from that of the third module (e.g., centrifugation in
the first module and cytometry in the third module). Additionally,
the first module takes twice as long to complete. In that time
period, the third module processes a second sample.
The second module starts processing a sample at a time that is
later than the start time of the first and third modules. This may
be the case if, for example, the second module requires a period
for completion of sample processing that is different from that of
the first and third modules, or if the second module experiences a
malfunction.
The modules may have the same dimensions (e.g., length, width,
height) or different dimensions. In an example, a general or
special-use module has a length, width and/or height that is
different from that of another general or special-use module.
In some situations, systems and modules for processing biological
samples are configured to communicate with other systems to
facilitate sample processing (e.g., preparation, assaying). In an
embodiment, a system communicates with another system by way of a
wireless communication interface, such as, e.g., a wireless network
router, Bluetooth, radiofrequency (RF), opto-electronic, or other
wireless modes of communication. In another embodiment, a system
communicates with another system by way of a wired communication,
such as a wired network (e.g., the Internet or an intranet).
In some embodiments, point of service devices in a predetermined
area communicate with one another to facilitate network
connectivity, such as connectivity to the Internet or an intranet.
In some cases, a plurality of point of service devices communicate
with one another with the aid of an intranet, such as an intranet
established by one of the plurality of point of service devices.
This may permit a subset of a plurality of point of service devices
to connect to a network without a direct (e.g., wired, wireless)
network connection--the subset of the plurality of point of service
devices connect to the network with the aid of the network
connectivity of a point of service device connected to the network.
With the aid of such shared connectivity, one point of service
device may retrieve data (e.g., software, data files) without
having to connect to a network. For instance, a first point of
service device not connected to a wide-area network may retrieve a
software update by forming a local-area connection or a
peer-to-peer connection to a second point of service device. The
first point of service device may then connect to the wide-area
network (or cloud) with the aid of the network connectivity of the
second point of service device. Alternatively, the first point of
service device may retrieve a copy of the software update directly
from the second point of service device.
In an example of shared connectivity, a first point of service
devices connects (e.g., wireless connection) to a second point of
service device. The second point of service device is connected to
a network with the aid of a network interface of the second point
of service device. The first point of service device may connect to
the network through the network connection of the second point of
service device.
Components
A device may comprise one or more components. One or more of these
components may be module components, which may be provided to a
module. One or more of these components are not module components,
and may be provided to the device, but external to the module.
Examples of device components may include a fluid handling system,
tips, vessels, microcard, assay units (which may be in the forms of
tips or vessels), reagent units (which may be in the form of tips
or vessels), dilution units (which may be in form of tips or
vessels), wash units (which may in the form of tips or vessels),
contamination reduction features, lysing features, filtration,
centrifuge, temperature control, detector, housing/support,
controller, display/user interface, power source, communication
units, device tools, and/or device identifier.
One, two, or more of the device components may also be module
components. In some embodiments, some components may be provided at
both the device level and module level and/or the device and module
may be the same. For example, a device may have its own power
source, while a module may also have its own power source.
FIG. 2 provides a high level illustration of a device 200. The
device may have a housing 240. In some embodiments, one or more
components of the device may be contained within the device
housing. For example, the device may include one or more support
structure 220, which may have one or more module 230a, 230b. The
device may also have a sample collection unit 210. A device may
have a communication unit 280 capable of permitting the device to
communicate with one or more external device 290. The device may
also include a power unit 270. A device may have a display/user
interface 260 which may be visible to an operator or user of the
device. In some situations, the user interface 260 displays a user
interface, such as graphical user interface (GUI), to a subject.
The device may also have a controller 250 which may provide
instructions to one or more component of the device.
In some embodiments, the display unit on the device may be
detachable. In some embodiments, the display unit may also have a
CPU, memory, graphics processor, communication unit, rechargeable
battery and other peripherals to enable to operate it as a "tablet
computer" or "slate computer" enabling it to communicate wirelessly
to the device. In some embodiments, the detached display/tablet may
be a shared source amongst all devices in one location or a group
so one "tablet" can control, input and interact with 1, 2, 5, 10,
100, 1000 or more devices.
In some embodiments, the detached display may act as companion
device for a healthcare professional to not only control the
device, but also act as touch-enabled input device for capturing
patient signatures, waivers and other authorizations and
collaborating with other patients and healthcare professionals.
The housing may surround (or enclose) one or more components of the
device.
The sample collection unit may be in fluid communication with one
or more module. In some embodiments, the sample collection unit may
be selectively in fluid communication with the one or more module.
For example, the sample collection unit may be selectively brought
into fluid communication with a module and/or brought out of fluid
communication with the module. In some embodiments, the sample
collection unit may be fluidically isolated from the module. A
fluid handling system may assist with transporting a sample from a
sample collection unit to a module. The fluid handling system may
transport the fluid while the sample collection unit remains
fluidically or hydraulically isolated from the module.
Alternatively, the fluid handling system may permit the sample
collection unit to be fluidically connected to the module.
The communication unit may be capable of communicating with an
external device. Two-way communication may be provided between the
communication unit and the external device.
The power unit may be an internal power source or may be connected
to an external power source.
Further descriptions of a diagnostic device and one or more device
components may be discussed in greater detail elsewhere herein.
Fluid Handling System
A device may have a fluid handling system. As previously described,
any discussion herein of fluid handling systems may apply to any
sampling handling system or vice versa. In some embodiments, a
fluid handling system may be contained within a device housing. The
fluid handling system or portions of the fluid handling system may
be contained within a module housing. The fluid handling system may
permit the collection, delivery, processing and/or transport of a
fluid, dissolution of dry reagents, mixing of liquid and/or dry
reagents with a liquid, as well as collection, delivery, processing
and/or transport of non-fluidic components, samples, or materials.
The fluid may be a sample, a reagent, diluent, wash, dye, or any
other fluid that may be used by the device. A fluid handled by the
fluid handling system may include a homogenous fluid, or fluid with
particles or solid components therein. A fluid handled by a fluid
handling system may have at least a portion of fluid therein. The
fluid handling system may be capable of handling dissolution of dry
reagents, mixing of liquid and/or dry reagents in a liquid.
"Fluids" can include, but not limited to, different liquids,
emulsions, suspensions, etc. Different fluids may be handled using
different fluid transfer devices (tips, capillaries, etc.). A fluid
handling system, including without limitation a pipette, may also
be used to transport vessels around the device. A fluid handling
system may be capable of handling flowing material, including, but
not limited to, a liquid or gaseous fluid, or any combination
thereof. The fluid handling system may dispense and/or aspirate the
fluid. The fluid handling system may dispense and/or aspirate a
sample or other fluid, which may be a bodily fluid or any other
type of fluid. The sample may include one or more particulate or
solid matter floating within a fluid.
In one example, the fluid handling system may use a pipette or
similar device. A fluid handling device may be part of the fluid
handling system, and may be a pipette, syringe, capillary, or any
other device. The fluid handling device may have portion with an
interior surface and an exterior surface and an open end. The fluid
handling system may also contain one or more pipettes, each of
which has multiple orifices through which venting and/or fluid
flows may happen simultaneously. In some instances, the portion
with an interior surface and an exterior surface and open end may
be a tip. The tip may or may not be removable from a pipette
nozzle. The open end may collect a fluid. The fluid may be
dispensed through the same open end. Alternatively, the fluid may
be dispensed through another end.
A collected fluid may be selectively contained within the fluid
handling device. The fluid may be dispensed from the fluid handling
device when desired. For example, a pipette may selectively
aspirate a fluid. The pipette may aspirate a selected amount of
fluid. The pipette may be capable of actuating stirring mechanisms
to mix the fluid within the tip or within a vessel. The pipette may
incorporate tips or vessels creating continuous flow loops for
mixing, including of materials or reagents that are in non-liquid
form. A pipette tip may also facilitate mixture by metered delivery
of multiple fluids simultaneously or in sequence, such as in 2-part
substrate reactions. The fluid may be contained within a pipette
tip, until it is desired to dispense through fluid from the pipette
tip. In some embodiments, the entirety of the fluid within the
fluid handling device may be dispensed. Alternatively, a portion of
the fluid within the fluid handling device may be dispensed. A
selected amount of the fluid within the fluid handling device may
be dispensed or retained in a tip.
A fluid handling device may include one or more fluid handling
orifice and one or more tip. For example, the fluid handling device
may be a pipette with a pipette nozzle and a removable/separable
pipette tip. The tip may be connected to the fluid handling
orifice. The tip may be removable from the fluid handling orifice.
Alternatively, the tip may be integrally formed on the fluid
handling orifice or may be permanently affixed to the fluid
handling orifice. When connected with the fluid handling orifice,
the tip may form a fluid-tight seal. In some embodiments, a fluid
handling orifice if capable of accepting a single tip.
Alternatively, the fluid handling orifice may be configured to
accept a plurality of tips simultaneously.
The fluid handling device may include one or more fluidically
isolated or hydraulically independent units. For example, the fluid
handling device may include one, two, or more pipette tips. The
pipette tips may be configured to accept and confine a fluid. The
tips may be fluidically isolated from or hydraulically independent
of one another. The fluid contained within the tips may be
fluidically isolated or hydraulically independent from one another
and other fluids within the device. The fluidically isolated or
hydraulically independent units may be movable relative to other
portions of the device and/or one another. The fluidically isolated
or hydraulically independent units may be individually movable.
A fluid handling device may include one, two, three, four or more
types of mechanisms in order to dispense and/or aspirate a fluid.
For example, the fluid handling device may include a positive
displacement pipette and/or an air displacement pipette. The fluid
handling device may include piezo-electric or acoustic dispensers
and other types of dispensers. The fluid handling device may
include, one, two, three, four, five, six, seven, eight, nine, ten,
or more positive displacement pipettes. The fluid handling device
may be capable of metering (aspirating) very small droplets of
fluid from pipette nozzles/tips. The fluid handling device may
include one or more, two or more, 4 or more, 8 or more, 12 or more,
16 or more, 20 or more, 24 or more, 30 or more, 50 or more, or 100
or more air displacement pipettes. In some embodiments, the same
number of positive displacement pipettes and air displacement
pipettes may be used. Alternatively, more air displacement pipettes
may be provided than positive displacement pipettes, or vice versa.
In some embodiments, one or more positive displacement pipette can
be integrated into the "blade" style (or modular) pipetter format
to save space and provide additional custom configurations.
In some embodiments, a fluid handling apparatus, such as a pipette
(e.g., a positive displacement pipette, air displacement pipette,
piezo-electric pipette, acoustic pipette, or other types of
pipettes or fluid handling apparatuses) described elsewhere herein,
may have the capability of picking up several different liquids
with or without separation by air "plugs." A fluid handling
apparatus may have the capability of promoting/accelerating
reaction with reagents attached to surface (e.g., pipette tip
surfaces) by reciprocating movement of the enclosed liquid, thus
breaking down an unstirred layer. The reciprocating movement may be
driven pneumatically. The motion may be equivalent or comparable to
orbital movement of microtiter places to accelerate binding
reactions in ELISA assays.
A fluid handling device may comprise one or more base or support.
The base and/or support may support one or more pipette head. A
pipette head may comprise a pipette body and a pipette nozzle. The
pipette nozzle may be configured to interface with and/or connect
to a removable tip. The base and/or support may connect the one or
more pipette heads of the fluid handling device to one another. The
base and/or support may hold and/or carry the weight of the pipette
heads. The base and/or support may permit the pipette heads to be
moved together. One or more pipette head may extend from the base
and/or support. In some embodiments, one or more positive
displacement pipette and one or more air displacement pipette may
share a base or support.
FIG. 12 shows an example of a fluid handling apparatus in a
collapsed position, provided in accordance with another embodiment
of the invention. The fluid handling apparatus may include one or
more tips 4610, 4612, 4614. In some embodiments, a plurality of tip
types may be provided. For example, a positive displacement tip
4610 may be provided, an air displacement nozzle tip 4612, and an
air displacement mini-nozzle tip 4614 may be provided. A base 4620
may be provided, supporting one or more pipette head. A positive
displacement motor 4630 may be coupled to a positive displacement
pipette head 4635.
A fluid handling apparatus may include a manifold 4640. The
manifold may include one or more vent ports 4642. A vent port may
be fluidically connected to the fluid path of a pipette head. In
some embodiments, each pipette head may have a vent port. In some
instances, each air displacement pipette head may have a vent port.
A tubing 4644 may be connected to the manifold. The tubing may
optionally connect the manifold to a positive or negative pressure
source, ambient air, or a reversible positive/negative pressure
source.
A thermal spreader 4650 may be provided for a fluid handling
apparatus. The thermal spreader may provide isothermal control. In
some embodiments, the thermal spreader may be in thermal
communication with a plurality of pipette heads. The thermal
spreader may assist with equalizing temperature of the plurality of
pipette heads.
A fluid handling apparatus may have one or more support portion. In
some embodiments, the support portion may include an upper
clamshell 4660 and a lower clamshell 4665.
FIG. 12A shows a collapsed fluid handling apparatus as previously
described, in a fully retracted position. FIG. 12B shows a
collapsed fluid handling apparatus, in a full z-drop position. In a
full z-drop position, an entire lower clamshell 4665 may be lowered
relative to the upper clamshell 4660. The lower clamshell may
support the pipette heads and nozzles. The pipette heads and
nozzles may move with the lower clamshell. The lower clamshell may
include a front portion 4667 which supports the pipette heads, and
a rear portion 4668 which supports an actuation mechanism and
switching mechanisms.
FIG. 13 shows an example of a fluid handling apparatus in an
extended position in accordance with an embodiment of the
invention. The fluid handling apparatus may include one or more
tips 4710, 4712, 4714. A positive displacement tip 4710 may be
provided, an air displacement nozzle tip 4712, and an air
displacement mini-nozzle tip 4714 may be provided. The fluid
handling apparatus may also include one or more nozzles 4720, 4722,
4724. A positive displacement nozzle 4720, an air displacement
nozzle 4722, and an air displacement mini-nozzle 4724 may be
provided. The nozzles may interface with their respective tips. In
some instances, the nozzles may connect to their respective tips
via press-fit or any other interface mechanism. One or more tip
ejector 4732, 4734 may be provided. For example, a regular tip
ejector 4732 may be provided for removing an air displacement tip
4712. One or more mini-ejector 4734 may be provided for removing an
air displacement mini-tip 4714. The ejectors may form collars. The
ejectors may be designed to push the tips off. The ejectors may be
located beneath the nozzles.
The fluid handling apparatus may be in a full z-drop position with
a lower clamshell 4765 lowered relative to an upper clamshell 4760.
Furthermore, a z-clutch-bar 4770 may be provided which may engage
any or all of the pipettes for individualized and/or combined
nozzle drop (i.e. nozzle extension). FIG. 13 shows an example where
all nozzles are dropped. However, the nozzles may be individually
selectable to determine which nozzles to drop. The nozzles may drop
in response to a single actuation mechanism, such as a motor. A
switching mechanism may determine which pipettes are engaged with
the bar. The clutch bar 4770 illustrated shows the nozzles in a
dropped position, with the clutch bar lowered. A z-motor encoder
4780 may be provided. The encoder may permit the tracking of the
location of the motor movement.
An x-axis slider 4790 may be provided in accordance with some
embodiments. The x-axis slider may permit the fluid handling
apparatus to move laterally. In some embodiments, the fluid
handling apparatus may slide along a track.
FIG. 14 shows a front view of a fluid handling apparatus. A
protector plate 4810 may be provided in some embodiments. The
protector plate may protect portions of the pipette head. The
protector plate may protect a fluid path of the pipette head. In
one example, the protector plate may be provided for rigid tubing,
connecting pipette cavities to nozzles. The protector plate may be
connected to a thermal spreader or may be integrally incorporated
with a thermal spreader.
As previously described, multiple types of pipettes and/or tips may
be provided. One or more positive displacement pipette and/or one
or more air displacement pipettes may be used. In some instances,
the protector plate may only cover the air displacement pipettes.
Alternatively, the protector place may cover the positive
displacement pipette only, or may cover both.
FIG. 15 shows a side view of a fluid handling apparatus. A fluid
handling apparatus may include a pipette head, which may include a
nozzle head 4902, which may be configured to connect to a tip 4904.
The tip may be removably connected to the pipette nozzle.
One or more pipette nozzle may be supported by a nozzle-drop shaft
4920. A z-motor 4922 may be provided, which when actuated, may
cause one or more nozzle to drop (e.g., extend). One or more
solenoid 4924, or other switching mechanism may be provided to
selectively connect the z-motor with the nozzle-drop shaft. When
the solenoid is in an "on" position, actuation of the z-motor may
cause the nozzle-drop shaft to be lowered or raised. When the
solenoid is in an "off" position, actuation of the z-motor does not
cause movement of the nozzle-drop shaft.
Tubing 4910 may be provided through the pipette head, and
terminating at the pipette nozzle. The tubing may have a portion
with rigid inner tubing 4910a, and rigid outer tubing 4910b. In
some instances, the rigid inner tubing may be movable while the
rigid outer tubing is stationary. In other embodiments, the rigid
inner tubing may be movable or stationary, and the rigid outer
tubing may be movable or stationary. In some embodiments, the inner
tubing may be movable relative to the outer tubing. The overall
length of the tubing may be variable.
A plunger 4930 may be provided within the fluid handling apparatus.
The plunger may provide metering within a pipette cavity. An
extension of the pipette cavity 4935 may be provided. In some
instances, the extension of the pipette cavity may be in fluid
communication with the tubing 4910. Alternatively, the tubing and
the pipette cavity are not in fluid communication. In some
embodiments, the pipette cavity and the tubing are parallel to one
another. In other embodiments, the pipette cavity and the tubing
are substantially non-parallel to one another. They may be
substantially perpendicular to one another. The tubing may have a
substantially vertical orientation while the pipette cavity may
have a substantially horizontal orientation, or vice versa. In some
embodiments, a pipette and tip may act in a push/pull fashion, such
as in a multi-lumen tubing arrangement, to aspirate and dispense
simultaneously or sequentially.
One or more valves 4937 may be provided for controlling vent port
access to the pipettes. In some instances, a valve may correspond
to an associated pipette. A valve may determine whether a vent port
is open or closed. A valve may determine the degree to which a vent
port is open. The vent port may be in communication with a pressure
source, such as a positive or negative pressure source. The vent
port may be in communication with ambient air. The vent port may
provide access to a tubing 4910 from a manifold.
A clutch-bar 4940 for individual metering may be provided. The
clutch bar may be connected to a motor that may be used to drive
the metering of the fluid. A guide shaft 4942 may optionally be
provided. One or more solenoid 4945 or other switching mechanism
may be provided in communication with the clutch-bar. The solenoid
or other switching mechanism may be provided to selectively connect
the motor with the plunger 4930. When the solenoid is in an "on"
position, actuation of the metering motor may cause the plunger to
be engaged and move to dispense and/or aspirate a fluid. When the
solenoid is in an "off" position, actuation of the metering motor
does not cause movement of the plunger. A plurality of plungers may
be provided, each being associated with its respective solenoid,
which may selectively be in an on or off position. Thus, when a
motor is actuated, only the plungers associated with "on" solenoids
may respond.
FIG. 16 shows another side view of a fluid handling apparatus. The
view includes a view of the motor 5010 used for metering. The motor
may be used for metering fluid within the air displacement
pipettes. An encoder 5020 for the motor is also illustrated. The
encoder may permit the tracking of the motor movement. This ensures
that the plunger position is known at all times.
FIG. 17 shows a rear perspective view of a fluid handling
apparatus. The fluid handling apparatus may include a pump 5110.
The pump may be in fluid communication with a pipette cavity. In
some instances, the pump may be brought into or out of fluid
communication with the pipette cavity. The pump may be in fluid
communication with a manifold, and/or vent port. The pump may pump
(or effect the movement of) liquid or air.
The pump may provide positive pressure and/or negative pressure.
The pump may be a reversible pump that may be capable of providing
both positive and negative pressure. The pump may be actuated in
pipettes containing pistons to permit the pipette to aspirate or
dispense any volume of liquid, without limitation by the positive
displacement that a given piston size is capable of generating.
This factor, in combination with large volume tips, could permit a
small pipette to aspirate or dispense large volumes of liquid for
certain applications. The pump may permit the pipette to function
without motor or piston, while still providing fine control through
pulse-width modulation.
A fluid handling apparatus may also include an accumulator 5120
with one or more valves that may connect to a pressure source or
ambient conditions. The accumulator may optionally connect to the
reversible pump, which may provide positive or negative
pressure.
A multi-headed fluid handling apparatus, such as a multi-headed
pipette may be capable of picking up multiple tips/vessels on
several pipette nozzles at the same time. For example, multiple
pipette nozzles may extend to pick up multiple tips/vessels. The
multiple pipette nozzles may be individually controllable to
determine which tips/vessels are picked up. Multiple tips/vessels
may be picked up simultaneously. In some instances, all pipette
nozzles may pick up pipette tips/vessels substantially
simultaneously.
In some embodiments, pipettes do not include plungers. A sample
(e.g., fluid) may be moved in or with the aid of the pipette using
positive and/or negative pressure. In some situations, positive or
negative pressure is provided with the aid of a gas or vacuum,
respectively. Vacuum may be provided using a vacuum system having
one or more vacuum pumps. Positive pressure may be provided with
the aid of pressurized air. Air may be pressurized using a
compressor.
Dimensions/Ranges
One or more dimensions (e.g., length, width, or height) of a
pipette may be less than or equal to about 1 mm, 5 mm, 10 mm, 15
mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm,
70 mm, 80 mm, 90 mm, 100 mm, 112 mm, 12 cm, 15 cm, 20 cm, 25 cm, 30
cm, or any other dimension described elsewhere herein. One or more
dimensions may be the same, or may vary. For example, the height of
a pipette may not exceed 1 mm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 5.5
cm, 6 cm, 6.5 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 15
cm, 17 cm, 20 cm, 25 cm, or 30 cm.
In some embodiments, a pipette may have a total volume of 1
cm.sup.3 or less, 5 cm.sup.3 or less, 8 cm.sup.3 or less, 10
cm.sup.3 or less, 15 cm.sup.3 or less, 20 cm.sup.3 or less, 25
cm.sup.3 or less, 30 cm.sup.3 or less, 35 cm.sup.3 or less, 40
cm.sup.3 or less, 50 cm.sup.3 or less, 60 cm.sup.3 or less, 70
cm.sup.3 or less, 80 cm.sup.3 or less, 90 cm.sup.3 or less, 100
cm.sup.3 or less, 120 cm.sup.3 or less, 150 cm.sup.3 or less, 200
cm.sup.3 or less, 250 cm.sup.3 or less, 300 cm.sup.3 or less, or
500 cm.sup.3 or less.
The pipette may have one or more pipette head. In some embodiments,
an individual pipette head of the pipette may be able to dispense
any volume of fluid. For example, the individual pipette head may
be capable of dispensing and/or aspirating fluids of no more than
and/or equal to about 10 mL, 5 mL, 3 mL, 2 mL, 1 mL, 0.7 mL, 0.5
mL, 0.4 mL, 0.3 mL, 250 .mu.L, 200 .mu.L, 175 .mu.L, 160 .mu.L, 150
.mu.L, 140 .mu.L, 130 .mu.L, 120 .mu.L, 110 .mu.L, 100 .mu.L, 70
.mu.L, 50 .mu.L, 30 .mu.L, 20 .mu.L, 10 .mu.L, 7 .mu.L, 5 .mu.L, 3
.mu.L, 1 .mu.L, 500 nL, 300 nL, 100 nL, 50 nL, 10 nL, 5 nL, 1 nL,
500 pL, 100 pL, 50 pL, 10 pL, 5 pL, 1 pL, or any other volume
described elsewhere herein. The pipette may be capable of
dispensing no more than, and/or equal to any fluid volume, such as
those as described herein, while having any dimension, such as
those described elsewhere herein. In one example, a fluid handling
apparatus may have a height, width, and/or length that does not
exceed 20 cm and a pipette head which may be capable of aspirating
and/or dispensing at least 150 .mu.L.
The fluid handling system may be able to dispense and/or aspirate
fluid with great precision and/or accuracy. For example,
coefficient of variation of the fluid handling system may be less
than or equal to 20%, 15%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%,
2%, 1.5%, 1%, 0.7%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.07%, 0.05%,
0.01%, 0.005%, or 0.001%. A fluid handling apparatus may be capable
of dispensing and/or aspirating a fluid while functioning with a
coefficient of variation value as described herein. The fluid
handling system may be able to control the volume of fluid
dispensed to within 5 mL, 3 mL, 2 mL, 1 mL, 0.7 mL, 0.5 mL, 0.3 mL,
0.1 mL, 70 .mu.L, 50 .mu.L, 30 .mu.L, 20 .mu.L, 10 .mu.L, 7 .mu.L,
5 .mu.L, 3 .mu.L, 1 .mu.L, 500 nL, 300 nL, 100 nL, 50 nL, 10 nL, 5
nL, 1 nL, 500 pL, 100 pL, 50 pL, 10 pL, 5 pL, or 1 pL. For example,
the fluid handling apparatus may be capable of dispensing and/or
aspirating a minimum increment of no more than any of the volumes
described herein.
The fluid handling system may be capable of operating with any of
the coefficient of variations described herein and/or controlling
the volume of fluid dispensed to any value described herein while
having one or more other feature described (e.g., having any of the
dimensions described herein or being capable of dispensing and/or
aspirating any volume described herein). For example, a fluid
handling apparatus may be capable of dispensing and/or aspirating 1
.mu.L-3 mL of fluid while functioning with a coefficient of
variation of 4% or less.
A fluid handling apparatus may include one pipette head or a
plurality of pipette heads. In some embodiments, the plurality of
pipette heads may include a first pipette head and a second pipette
head. The first and second pipette heads may be capable of and/or
configured for dispensing and/or aspirating the same amount of
fluid. Alternatively, the first and second pipette heads may be
capable of and/or configured for dispensing different amounts of
fluid. For example, the first pipette head may be configured to
dispense and/or aspirate up to a first volume of fluid, and the
second pipette head may be configured to dispense and/or aspirate
up to a second volume of fluid, wherein the first and second
volumes are different or the same. In one example, the first volume
may be about 1 mL, while the second volume may be about 250
.mu.L.
In another example, the fluid handling apparatus may include a
plurality of pipette heads, wherein a first pipette head may
comprise a first pipette nozzle configured to connect with a first
removable tip, and a second pipette head may comprise a second
pipette nozzle configured to connect with a second removable tip.
The first removable tip may be configured to hold up to a first
volume of fluid, and the second removable tip may be configured to
hold up to a second volume of fluid. The first and second volumes
may be the same or may be different. The first and second volumes
may have any value as described elsewhere herein. For example, the
first volume may be about 1 mL, while the second volume may be
about 250 .mu.L.
A plurality of pipette heads may be provided for a fluid handling
apparatus. The plurality of pipette heads may be any distance
apart. In some embodiments, the fluid handling apparatus may be
less than or equal to about 0.1 mm, 0.3 mm, 0.5 mm, 0.7 mm, 1 mm,
1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm, 6 mm, 7 mm,
8 mm, 9 mm, 10 mm, 12 mm, 15 mm, 20 mm, 30 mm, or 50 mm. The
distance between the pipette heads may be from center to center of
the pipette heads. The distance between the pipette heads from
center to center may be the pitch of the pipette heads.
The pipette heads may share a support structure. In some
embodiments, the support structure may be a movable support
structure. One, two or more pipette heads may be movable along the
support structure so that the lateral distance between the pipette
heads may be variable. In some instances, the pitch of the pipette
heads may be variable to encompass or be limited by one or more of
the dimensions previously described. In one example, the pipette
heads may be slidable along the support so that the distances from
center to center of the pipette heads may vary. Each of the pipette
heads may be variable so that they are the same distance apart, or
may be individually variable so that they may be at various
distances apart. A lateral distance proportion between the pipette
heads may remain the same as pipette head positions vary, or may
change. Pipettes, blades, or nozzles may change their relative
position (move in or out, expand or shrink) to achieve different
pitches as needed and may access resources in multiple planes at
one time.
In some embodiments, the form factors of pipettes (e.g., positive
displacement pipette, suction-type pipette, air displacement
pipette) may be suitable for so-called "mini" pipettes. The form
factors in such cases may be reduced and optimized for space
through horizontal or clamshell configurations. Systems or devices
may include one or a plurality of mini pipettes. The mini pipettes
may be modular and removable from supporting structures having the
mini pipettes.
In some embodiments, a mini pipette is configured to handle a
sample of 1 uL, 0.9 uL, 0.8 uL, 0.7 uL, 0.6 uL, 0.5 uL, 0.4 uL, 0.3
uL, 0.2 uL, 0.1 uL, 10 nL, 1 nL.
In some embodiments, a mini pipette is provided that enables
macro-scale protocol and/or processing of various chemistries at a
point of service location as opposed to microfluidic-restricted
processing, which may not replicate lab protocols. In some
situations, the protocol and/or processing is selected from,
without limitation: centrifugation, separation, precipitation,
denaturation, extraction, coacervation, flocculation,
chromatography, column based processing, elutions, dilutions,
mixing, incubations, cell lysis, fixation of cells, heating,
cooling, distribution of sample, separate processing or assay or
detection systems, modularity, efficiency of sample utilization,
sedimentation, concentration of analyte on solid phase,
immunoassay, nucleic acid amplification, nuclear magnetic
resonance, microscopy, spectrometry, calorimetry, sequencing,
pathological oversight and analyses, and culture.
Pipette Configuration
A fluid handling apparatus may be a pipette. In some embodiments, a
fluid handling apparatus may comprise one or more pipette head. A
fluid handling apparatus may include a supporting body, and
extending therefrom, the one or more pipette heads. As previously
described, the supporting body may support the weight of the one or
more pipette heads. The supporting body may contain mechanisms for
moving the pipette heads independently or together in one dimension
or multiple dimensions. The supporting body may permit the pipette
heads to move together. The supporting body may also be flexible or
"snake-like" and/or robotic in nature, permitting the pipette heads
a wide range of movement in multiple (or infinite) directional
planes. This range of movement may permit the pipettes to serve as
robotic end effectors for the device with one or more fluid
handling or non-fluid handling functions. The supporting body may
connect the pipette heads to one another. The shared supporting
body may or may not be integrally formed with the pipette heads.
The supporting body may or may not also support an actuation
mechanism. The supporting body may or may not be capable of
supporting the weight of actuation mechanism that may be operably
connected to one or more pipette head.
A pipette head may comprise a pipette nozzle configured to connect
with a removable tip. The pipette head may also include a pipette
body. The pipette nozzle may be coaxial with the pipette body. The
pipette body may support the pipette nozzle. The pipette nozzle may
include an opening. The pipette head may also include a fluid path
therein. The fluid path may or may not be contained within the
pipette body.
The fluid path may pass through the pipette body. The fluid path
may have a given length. The fluid path may terminate at the
pipette nozzle. The fluid path may be within an inner tubing. The
inner tubing may be rigid or flexible.
The pipette nozzle may connect with the removable tip in any
manner. For example, the pipette nozzle may connect with the
removable tip to form a fluid-tight seal. The removable tip may be
friction-fit with the pipette nozzle. The tip may interface with
the pipette nozzle along an outer surface of the pipette nozzle,
inner surface of the pipette nozzle, or within a groove or
intermediate portion of the pipette nozzle. Alternatively, the
pipette nozzle may interface with the tip along the outer surface
of the tip, inner surface of the tip, or within a groove or
intermediate portion of the tip.
In some embodiments, a plunger may be provided within a pipette
head. The plunger may permit the dispensing and/or aspiration of
fluid. The plunger may be movable within the pipette head. The
pipette may be capable of loading the desired plunger from a
selection of plungers, that are either stored in the pipette or
picked up from a storage area outside the pipette. The plunger may
be movable along a fluid path. The plunger may remain in the same
orientation, or may have varying orientations. In alternate
embodiments, a transducer-driven diaphragm may be provided which
may affect a fluid to be dispensed and/or aspirated through the
tip. Alternate dispensing and/or aspiration mechanisms may be used,
which may include a positive and/or negative pressure source that
may be coupled to a fluid path.
In some embodiments, the tip of the pipette head may have a length.
The direction of tip may be along the length of the tip. In some
embodiments, the fluid handling apparatus may include a motor
having a rotor and stator. The rotor may be configured to rotate
about an axis of rotation. The axis of rotation may have any
orientation with respect to the tip. For example, the axis of
rotation may be substantially parallel to the tip. Alternatively,
the axis of rotation may be substantially non-parallel to the tip.
In some instances, the axis of rotation may be substantially
perpendicular to the tip, or any other angle with respect to the
tip including but not limited to 15 degrees, 30 degrees, 45
degrees, 60 degrees, or 75 degrees. In one example, the axis of
rotation may be horizontal, while the removable tip may be aligned
vertically. Alternatively, the axis of rotation may be vertical
while the removable tip is aligned horizontally. This configuration
may provide a "bent" pipette configuration where the tip is bent
relative to the motor. The motor may be useful for metering fluid
within the tip. In some embodiments, the motor may permit the
movement of one or more plunger within a pipette head.
In some embodiments, the fluid handling apparatus may include a
motor that may be capable of permitting the movement of a plurality
of plungers that are not substantially parallel to the removable
tip. Alternatively, the movement of the plurality of plungers may
be substantially parallel to the removable tip. In some instances,
the movement of the plurality of plungers may be substantially
perpendicular to the removable tip, or any other angle, including
but not limited to those mentioned elsewhere herein. In one
example, the plunger may be capable of moving in a horizontal
direction, while the removable tip is aligned vertically.
Alternatively, the plunger may be capable of moving in a vertical
direction while the removable tip is aligned horizontally.
A fluid path may terminate at a pipette nozzle. In some instances,
another terminus of the fluid path may be provided at the plunger.
In some embodiments, the fluid path may be bent or curved. A first
portion of a fluid path may have a different orientation than a
second portion of the fluid path. The first and second portions may
be substantially perpendicular to one another. The angles of the
first and second portions may be fixed relative to one another, or
may be variable.
Actuation
A fluid handling apparatus may include an actuation mechanism. In
some embodiments, a single actuation mechanism may be provided for
the fluid handling apparatus. Alternatively, a plurality of
actuation mechanisms may be provided. In some instances, only a
single actuation mechanism may be provided per particular use
(e.g., tip removal, plunger control, switch control).
Alternatively, multiple actuation mechanisms may be provided for a
particular use. In one example, an actuation mechanism may be a
motor. The motor may include a rotor and stator. The rotor may be
capable of rotating about an axis of rotation.
A single actuation mechanism, such as a motor, may be useful for
individualized dispensing and/or aspiration. A fluid handling
apparatus may include a plurality of pipette heads. A plurality of
plungers may be provided, wherein at least one plunger may be
within a pipette head and configurable to be movable within the
pipette head. In some instances, each of the pipette heads may have
one or more plungers therein. The plurality of plungers may be
independently movable. In some instances, the plungers may move
along a fluid path within the pipette head. The actuation mechanism
may be operably connected to the plungers. The actuation mechanism
may permit the independent movement of the plurality of plungers.
The movement of such plungers may optionally cause the dispensing
and/or aspiration of fluid. A single motor or other actuation
mechanism may control the independent movement of a plurality of
plungers. In some instances, a single motor or other actuation
mechanism may control the independent movement of all of the
plungers within said plurality.
A single actuation mechanism, such as a motor, may be useful for
individualized removal of a tip from pipette nozzle. A fluid
handling apparatus may include a plurality of pipette heads. A
plurality of tip removal mechanisms may be provided, wherein at
least one tip removal mechanism is configured to remove an
individually selected tip from the pipette nozzle. The tip removal
mechanism may be configured to be movable with respect to the
pipette nozzle to effect said removal. The tip removal mechanisms
may be independently movable. Alternatively, the tip removal
mechanisms need not move, but may be independently controllable to
permit the removal of the tips. The actuation mechanism may be
operably connected to the tip removal mechanisms. The actuation
mechanism may permit the independent movement of the plurality of
tip removal mechanisms. A single motor or other actuation mechanism
may control the independent movement of a plurality of tip removal
mechanisms. In some instances, a single motor or other actuation
mechanism may control the independent movement of all of the tip
removal mechanisms within said plurality.
In some embodiments, a tip removal mechanism may be within a
pipette head. An internal tip removal mechanism may be configured
to be movable within the pipette head. For example, a tip removal
mechanism may be a plunger. In other embodiments, the tip removal
mechanism may be external to the pipette head. For example, the tip
removal mechanism may be a collar wrapping around at least a
portion of a pipette head. The collar may contact a portion of the
pipette nozzle, pipette body and/or pipette tip. Another example of
an external removal mechanism may be a stripping plate. A tip
removal mechanism may or may not contact the tip when causing the
tip to be removed from the pipette.
A single actuation mechanism, such as a motor, may be useful for
individualized retraction and/or extension of a pipette nozzle. A
fluid handling apparatus may include a plurality of pipette heads.
A pipette head may include a pipette nozzle which may or may not be
movable with respect to a support body. A plurality of pipette
nozzles may be independently movable. The actuation mechanism may
be operably connected to the pipette nozzles or other portions of a
pipette head that may permit the retraction and/or extension of a
pipette nozzle. The actuation mechanism may permit the independent
movement of the plurality of pipette nozzles. A single motor or
other actuation mechanism may control the independent movement of a
plurality of pipette nozzles. In some instances, a single motor or
other actuation mechanism may control the independent movement of
all of the pipette nozzles within said plurality.
In some embodiments, a tip may be connected to a pipette nozzle
based on the positions of the pipette nozzles. For example, a
pipette nozzle may be extended and brought down to contact a tip.
The pipette nozzle and tip may be press-fit to one another. If
selected pipette nozzles are independently controllable to be in an
extended position, the tips connected to the apparatus may be
controllable. For example, one or more pipette nozzle may be
selected to be extended. Tips may be connected to the extended
pipette nozzle. Thus, a single actuation mechanism may permit the
independent selection and connection/pick-up of tips.
Alternatively, a single motor or other actuation mechanism may
control the independent movement of a single plunger, tip removal
mechanism, and/or pipette nozzle. In some instances, a plurality of
actuation mechanisms may be provided to control the movement of a
plurality of plungers, tip removal mechanisms, and/or pipette
nozzles.
A fluid handling apparatus may include one or more switches. An
individual switch may have an on position and an off position,
wherein the on position may permit an action or movement in
response to movement by an actuation mechanism, and wherein the off
position does not permit an action or movement in response to
movement by the actuation mechanism. An on position of a switch may
permit an operable connection between the actuation mechanism, and
another portion of the fluid handling apparatus, such as a plunger,
tip removal mechanism, and/or pipette nozzle movement mechanism. An
off position of a switch may not permit an operable connection
between the actuation mechanism, and another portion of the fluid
handling apparatus, such as a plunger, tip removal mechanism,
and/or pipette nozzle movement mechanism. For example, an off
position may permit the actuation mechanism to move, but no
response is provided by the selected other portion of the fluid
handling mechanism. In one example, when a switch is in an on
position, one or more plunger associated with the individual switch
may move in response to a movement by a motor, and when the switch
is in an off position, one or more plunger associated with the
individual switch is not permitted to move in response to movement
by the motor. In another example, when a switch is in an on
position, one or more tip removal mechanism associated with the
individual switch may cause a tip to be removed in response to
movement by a motor, and when the switch is in an off position, one
or more tip removal mechanism may not cause a tip to be removed in
response to movement by the motor. Similarly, when a switch is in
an on position, one or more pipette nozzle associated with the
individual switch may extend and/or retract in response to a
movement by a motor, and when the switch is in an off position, one
or more pipette nozzle associated with the individual switch is not
permitted to extend and/or retract in response to movement by the
motor.
A switch may be a binary switch that may have only an on position
and an off position. One, two or more actuations may occur when a
switch is in an on position and may not occur when a switch is in
an off position. In alternate embodiments, a switch may have
multiple positions (e.g., three, four, five, six, seven, eight or
more positions). A switch may be completely off, completely on, or
partially on. In some embodiments, a switch may have different
degrees of depression. Different positions of the switch may or may
not permit different combinations of actuation. In one example, a
switch in a zero position may not permit actuation of a plunger and
of a tip removal mechanism, a switch in a one position may permit
actuation of a plunger while not permitting actuation of a tip
removal mechanism, a switch in a two position may not permit
actuation of a plunger while permitting actuation of a tip removal
mechanism, and a switch in a three position may permit actuation of
a plunger and permit actuation of a tip removal mechanism, when a
motor is actuated. In some embodiments, a switch may include a
control pin which may extend varying degrees to represent different
positions of the switch.
In some embodiments, the switch may be a solenoid. The solenoid may
have an on position and/or an off position. In some embodiments,
the solenoid may have an extended component for an on position, and
a retracted component for an off position. A single solenoid may be
provided for each pipette head. For example, a single solenoid may
or may not permit the movement of an individual plunger associated
with the solenoid, a tip removal mechanism associated with the
solenoid, or a pipette nozzle associated with the solenoid.
Multi-Use Transport
A fluid handling apparatus may be useful to dispense, aspirate,
and/or transfer one or more fluids. The fluid handling apparatus
may also be useful for one or more additional function, including
non-fluid handling functions. The connection of a component or tip
may permit the fluid handling device to function as a robot capable
of performing one or more non-fluid handling functions.
Alternatively, the pipette itself may be employed to perform one or
more such non-fluid handling functions by means of one or more
actuation mechanisms. Such non-fluid handling functions may include
the ability to transfer power to move components, tools or other
objects, such as a cuvette body, or cartridges or test samples, or
any component thereof. When combined with a flexible supporting
body (described herein) or other configuration allowing a wide
range of movement, the apparatus may be able to perform such
functions in multiple dimensions within the device, or even outside
it.
For instance, the fluid handling apparatus may be useful to
transfer a component from one location within the device, to
another. Components that may be transferred may be sample
processing components. A sample processing component may be a
sample preparation unit or component thereof, an assay unit
component thereof, and/or a detection unit or component thereof.
Examples of components may include but are not limited to tips,
vessels, support structures, micro cards, sensors, temperature
control devices, image capture units, optics, cytometers,
centrifuges, or any other components described elsewhere
herein.
The fluid handling apparatus may pick up a sample processing
component. The fluid handling apparatus may move the sample
processing component to a different location of the device. The
fluid handling apparatus may drop off the sample processing
component at its new location within the device.
The fluid handling apparatus may be capable of transferring sample
processing components within a module. The fluid handling apparatus
may or may not be confined to the module. Alternatively, the fluid
handling apparatus may be capable of transferring sample processing
components between modules, and need not be confined to a single
module. In some instances, the fluid handling apparatus may be
capable of transferring sample processing components within a rack
and/or may be confined to a rack. Alternatively, the fluid handling
apparatus may be capable of transferring sample processing
components between racks, and need not confined to a single
rack.
A fluid handling apparatus may pick up and move a sample processing
component using various mechanisms. For example, the sample
processing component may be picked up using a press-fit between one
or more of the pipette heads and a feature of the sample processing
component. For example, a pipette nozzle may interface with a tip
through a press-fit arrangement. The same press-fit arrangement may
be used to permit a pipette nozzle and a feature of the sample
processing component to engage. Alternatively, the press-fit
interface may occur between any other portion of the fluid handling
apparatus and the sample processing component. In some instances,
the press-fit feature of the sample processing component may be
protruding to encounter the fluid handling apparatus. The press-fit
feature of the sample processing component may have a shape
complementary to the press-fit portion of the fluid handling
apparatus.
Another example of an interface mechanism may be a pressure-driven
mechanism, such as a suction mechanism. The sample processing
component may be picked up using a suction provided by one, two or
more of the pipette heads. The suction may be provided by one or
more pipette head may be provided by the internal actuation of a
plunger, or a negative pressure source coupled to the fluid path.
The pipette heads providing suction may contact any portion of the
sample processing component, or may contact a specific feature of
the sample processing component. The feature of the sample
processing component may or may not be protruding to encounter the
fluid handling apparatus.
An additional example of an interface mechanism may be a magnetic
mechanism. A fluid handling apparatus may include a magnet that may
be turned on to interface with a magnet of the sample processing
component. The magnet may be turned off when it is desired to drop
off the sample processing component. Additional mechanisms known in
the art including but not limited to adhesives, hook and loop
fasteners, screws, or lock and groove configurations may be
used.
In some embodiments, a component removal mechanism may be provided
to assist with dropping off the sample processing component.
Alternatively, no separate component removal mechanism may be
required. In some instances, a tip removal mechanism may be used as
a component removal mechanism. In another example, a plunger may be
used as a component removal mechanism. Alternatively, separate
component removal mechanisms may be provided. A component removal
mechanism may use the principles of gravity, friction, pressure,
temperature, viscosity, magnetism, or any other principles. A large
quantity of tips can be stored within the device that are available
as a shared resource to the pipette or robot to be utilized when
required. Tips may be stored in a hopper, cartridge, or bandoleer
to be used when required. Alternatively, tips may be stored in
nested fashion to conserve space within the device. In another
embodiment, a module can be configured to provide extra tips or any
other resources needed as a shared module in the device.
The fluid handling apparatus may interface with the sample
processing component at any number of interfaces. For example, the
fluid handling apparatus may interface with the sample processing
component at one, two, three, four, five, six, seven, eight, nine,
ten, or more interfaces. Each of the interfaces may be the same
kind of interface, or may be any combination of various interfaces
(e.g., press fit, suction, magnetic, etc.). The number and/or type
of interface may depend on the sample processing component. The
fluid handling apparatus may be configured to interface with a
sample processing component with one type of interface, or may have
multiple types of interface. The fluid handling apparatus may be
configured to pick up and/or transfer a single type of sample
processing component or may be capable of picking up and
transferring multiple types of sample processing components. The
fluid handling apparatus, assisted by the application of various
tips, may facilitate or perform various sample processing tasks for
or with the sample processing component, including physical and
chemical processing steps.
FIG. 18 provides an example of a fluid handling apparatus used to
carry a sample processing component. The sample processing
component may be a cuvette carrier 5210. The cuvette carrier may
have one or more interface feature 5212 that may be configured to
interface with the fluid handling device. In some embodiments, the
interface feature may contact a pipette nozzle 5220 of the fluid
handling device. A plurality of interface features may contact a
plurality of pipette nozzles.
In some embodiments, a tip removal mechanism 5230 may be useful for
removing the cuvette carrier from the pipette nozzle. A plurality
of tip removal mechanisms may be actuated simultaneously or in
sequence.
FIG. 19 shows a side view of a fluid handling apparatus useful for
carrying a sample processing component. A cuvette carrier 5310 may
interface with the fluid handling apparatus. For example, nozzles
5320 that may engage with the cuvette carrier. The nozzles may have
the same shape and/or configuration. Alternatively, the nozzles may
have varying configurations. The cuvette carrier may have one or
more complementary shape 5330, which may be configured to accept
the nozzles. The nozzles may be engaged with the carrier through
friction and/or vacuum assist. The nozzles may be for air
displacement pipettes.
The cuvette carrier may interface with one or more cuvette 5340, or
other types of vessels. The cuvette may have a configuration as
shown in FIGS. 27A-B.
The fluid handling apparatus may also interface with a series of
connected vessels. One such configuration is shown in FIG. 26,
where the fluid handling apparatus may interface with pick-up ports
6920 to pick up the strip of vessels.
In some embodiments, a mini vessel is provided that may interface
with a pipette for various processing and analytical functions. The
various processing and analytics functions in some cases can be
performed at a point of service location.
FIG. 21 provides an example of an expand/contract elastomer
deflection tip pickup. A tip 6400 may be picked up by a pipette
nozzle 6410. A portion of the tip may fit within a portion of the
nozzle. For example, a portion of the external surface of the tip
may contact an internal surface of the nozzle. Alternatively, a
portion of the nozzle may fit within a portion of the tip. For
example, a portion of the internal surface of the tip may contact
an external surface of the nozzle.
The nozzle may include a rigid material 6420 and an elastomeric
material 6430. The rigid material may be a rigid block or solid
material. The tip may be surrounded by the elastomeric material.
The rigid block may lie over the elastomeric material surrounding
the tip.
An actuator may provide a force 6440 that may compress the rigid
block 6420. The rigid block may be pressed toward the tip. Pressing
the rigid block may compress the elastomer 6430, causing a bulging
effect that may shrink the internal chamber of the elastomer.
Shrinking the internal chamber may cause the elastomer to securely
grip the tip 6400. Compressing the elastomer in a first direction
(e.g., toward the tip) may cause the elastomer to expand in a
second direction (e.g., perpendicular toward the tip), which may
result in a compression of the elastomer around the tip.
In order to drop the tip off, the force 6440 may be removed, which
may cause the rigid block to move away from the tip, and may
release the elastomer from its compressed state.
FIG. 22 provides an example of a vacuum gripper tip pickup. A tip
6500 may be provided, having a large head 6502. The large head may
have a large flat surface area.
The tip may engage with a nozzle 6510. The nozzle may have one or
more tunnel 6520 therein. In some instances, one, two, three, four,
five, six, seven, eight or more tunnels may be provided through the
nozzle. The tunnels may be spaced radially equally apart, or at
varying intervals. The tunnels may have the same or differing
diameters. A first end of a tunnel may be coupled to a pressure
source, while a second end of the tunnel may be facing the head
6502 of the tip. The pressure source may be a negative pressure
source. Tunnels may be connected to a lower pressure region,
creating a suction force, which may act on the flat head of the
tip. The suction force may provide a pulling force that may act
upwards to secure the tip to the nozzle.
In some embodiments, an O-ring 6530 may be provided. The O-ring or
other elastomeric member may be located between a nozzle and the
head of a tip. One or more groove or shelf may be provided in the
nozzle and/or tip to accommodate the O-ring. The O-ring may permit
a seal to be formed between the nozzle and tip. This may provide
fluid tight seal between a fluidic path 6540 within the nozzle and
a fluid path 6550 within the tip.
In order to drop off the tip from the nozzle, the tunnels may be
disconnected from the negative suction pressure source.
Alternatively, the pressure source itself may be turned off.
Such nozzle-tip connections and interfaces are provided by way of
example only. Additional tip-nozzle interfaces, and/or variations
or combinations of those described herein may be implemented. In
some embodiments, one or more components of a pipette may be
configured to be exchangeable. Such configurations may allow for
future versions of components of a pipette (e.g. nozzles) with
different functionality to be added to or exchanged on the
pipette.
Modular Fluid Handling
In some embodiments, one or more of the fluid handling apparatus
configurations described elsewhere herein may be implemented in a
modular fashion. For example, one or more pipette head may be
provided in a modular format. In some embodiments, a single pipette
module may have a single pipette head and/or nozzle thereon.
Alternatively, a single pipette module may have two, three, four,
five, six or more pipette heads and/or nozzles thereon. Pipette
modules may be stacked next to each other to form a multi-head
configuration. Individual pipette modules may be removable,
replaceable, and/or swappable. Individual pipette modules may each
have the same configuration or may have different configurations.
In some instances, different pipette modules may be swapped out for
others to provide different functionality. Pipette modules
described herein may also be referred to as "pipette cards,"
"cards," or "pipette units."
FIG. 23 provides an example of a pipette module in accordance with
an embodiment of the invention. The pipette module may include a
pipette body 6600 mounted on a support 6610. The support may
include or more guide rod 6612, track, screw, or similar feature.
The pipette body may be able to slide along the guide rod or
similar feature. Any description herein of guide rod may apply to
any other feature that may guide the motion of a pipette body. In
some instances, the pipette body may be able to travel upwards
and/or downwards relative to the support along the guide rod
In some instances, the support may also include a lead screw 6614.
The lead screw may interact with an actuation interface 6602 of the
pipette body. The actuation interface may contact the lead screw,
so that as the lead screw may turn, the actuation interface may
engage with the teeth of the screw and may cause the pipette body
to move up or down correspondingly. In some embodiments, the
actuation interface may be a spring-loaded flexure. The spring
loaded flexure may be biased against the screw, thereby providing a
strong flexible contact with the screw. The spring loaded flexture
may be configured for precise kinematic constraint. The screw may
turn in response to an actuation mechanism. In some embodiments,
the actuation interface may be connected to the pipette piston by
means of a magnet, offering sufficient degrees of freedom to limit
wear and extend the life of the mechanism. In some embodiments, the
actuation mechanism may be a motor, which may include any type of
motor described elsewhere herein. The motor may be directly
connected to the screw or may be connected via a coupling. The
actuation mechanism may move in response to one or more
instructions from a controller. The controller may be external to
the pipette module, or may be provided locally on the pipette
module.
The pipette body 6600 may include a chassis. The chassis may
optionally be a shuttle clamshell chassis. A nozzle 6620 may be
connected to the pipette body. The nozzle may extend from the
pipette body. In some embodiments, the nozzle may extend downward
from the pipette body. The nozzle may have a fixed position
relative to the pipette body. Alternatively, the nozzle may extend
and/or retract from the pipette body. The nozzle may have a fluid
pathway therein. The fluid pathway may be connected to a pipetting
piston. Any descriptions of plungers, pressure sources, or fluid
pathways described elsewhere herein may be used in a modular
pipette. In some embodiments, the pipette body may support a motor
6630, geartrain, valve 6632, lead screw, magnetic piston mounting
block, piston cavity block and valve mount 6634, and/or other
components. One or more of the components described herein may be
provided within a chassis of the pipette body.
The pipette body may also include a guide rail 6640. The guide rail
may permit a portion of the pipette to move relative to the pipette
body. In one example, the pipette nozzle may move up or down
relative to the pipette body. The pipette nozzle may be connected
to an internal assembly that may move along the guide rail. In some
embodiments, the guide rail 6640 may be configured to interface
with another mechanism that may prevent the pipette body from
rotating. The guide rail may be constrained by an exterior chassis,
which may constrain rotation about the guide rod.
FIG. 24A shows an example of modular pipette having a retracted
shuttle in a full dispense position. A pipette body 6700 may be at
an upward position relative to a support 6710. The pipette body may
include an actuation interface 6702 that may engage with a lead
screw 6714. When a shuttle is retracted, the actuation interface
may be at the top of the lead screw. The mount may have a guide rod
6712 which may assist with guiding the pipette body relative to the
mount.
FIG. 24B shows an example of modular pipette having a dropped
shuttle in a full dispense position. A pipette body 6700 may be at
a downward position relative to a support 6710. The pipette body
may include an actuation interface 6702 that may engage with a lead
screw 6714. When a shuttle is dropped, the actuation interface may
be at the bottom of the lead screw. The mount may have a guide rod
6712 which may assist with guiding the pipette body relative to the
mount.
The mount may be fully retracted, fully dropped, or have any
position therebetween. The screw may turn to cause the pipette body
to rise or lower relative to the mount. The screw may turn in a
first direction to cause the pipette body to rise, and may turn in
a second direction to cause the pipette body to drop. The screw may
stop turning at any point in order to provide a position of the
pipette body. The pipette body may drop with the nozzle, which may
allow for greater complexity with less relative motion.
A plurality of pipette modules may be provided in a fluid handling
system. The pipette modules may have a blade configuration. A thin
blade form factor may be provided so that any number of blades may
be stacked side by side in a modular fashion to create a pipetting
system where each nozzle can work or move independently. A single
blade may be composed of multiple tools (nozzle, end effectors,
etc.) that can be chosen for specific operations, thereby
minimizing the space required for the overall assembly. In some
embodiments, a blade may also function as a freezer, refrigerator,
humidifier, and/or incubator for samples and/or reagents held in
vessels and/or cartridges.
The plurality of pipette modules may or may not be located adjacent
to one another. In some embodiments, the pipette modules may be
narrow and may be stacked next to one another, to form a multi-head
pipette configuration. In some embodiments, a pipette module may
have a width of less than or equal to 1 .mu.m, 5 .mu.m, 10 .mu.m,
50 .mu.m, 100 .mu.m, 300 .mu.m, 500 .mu.m, 750 .mu.m, 1 mm, 1.5 mm,
2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 1
cm, 1.5 cm, 2 cm, 3 cm, or 5 cm. Any number of pipette modules may
be positioned together. For example, one or more, two or more,
three or more, four or more, five or more, six or more, seven or
more, eight or more, nine or more, ten or more, twelve or more,
fifteen or more, twenty or more, twenty-five or more, thirty or
more, fifty or more, seventy or more, one hundred or more pipette
modules may be positioned together. Additional pipette modules may
be positioned separately or together and optionally may have
varying nozzles with different dimensions and capabilities.
The separate pipette modules may be positioned adjacent to one
another and may or may not contact one another. The pipette modules
positioned together may or may not share a common support. The
pipette bodies of the pipette modules may be able to move
independently of one another up and down relative to the pipette
mounts. The nozzles of the pipette modules may be able to extend
and/or retract independently relative to the other pipette modules.
In some embodiments, a pipette comprising multiple pipette modules
on a common support may be configured such that any one of the
pipette modules is capable of contacting the same locations within
a device as may be contacted by one or more of the other pipette
modules. This configuration may be desirable, for example, as a
precaution for in the event that a pipette module becomes
non-functional, and it becomes desirable for another pipette module
of the same common support to take over for the non-functional
pipette.
The various pipette modules may have the same or different
configurations. The pipette nozzles of the pipette nozzles may be
the same or may vary. The pipette modules may be capable of
interfacing with multiple types of tips or with specialized tips.
The pipette modules may have the same or varying degrees of
sensitivity or coefficient of variation. The pipette modules may
have the same or different mechanisms for controlling the
aspiration and/or dispensing of a fluid (e.g., air displacement,
positive displacement, internal plunger, vertical plunger,
horizontal plunger, pressure source). The pipette modules may have
the same or different mechanisms for picking up or removing a tip
(e.g., press-fit, screw-in, smart material, elastomeric material,
click-fit, or any other interface described elsewhere herein or
otherwise).
A modular pipette may have motion that may be broken down into a
plurality of functions. For example motion may be broken into (1)
motion of a piston and piston block in a (z) direction to aspirate
and dispense fluid, and (2) motion of a shuttle assembly in a (z)
direction to allow the pipette module to engage with objects at
various heights and provide clearance when moving in (xy)
directions. In some embodiments, the (z) direction may be a
vertical direction, and (xy) directions may be horizontal
directions. The motion of the piston and piston block may be
parallel to the motion of the shuttle assembly. Alternatively, the
motion of the piston and piston block may be non-parallel and/or
perpendicular. In other embodiments, the motion of the piston and
piston block and/or the motion of the shuttle assembly may be
horizontal or may have any other orientation.
Piston motion may be achieved in a very compact, flat package via
the use of a gear train and lead screw stacked horizontally, for
example as illustrated in FIG. 23. A constant force spring,
compression spring, or wave spring may be used to remove backlash
in this assembly and may therefore provide significantly improved
accuracy/precision for aspiration and dispense. The system may use
exact or very precise kinematic constraint with various springs in
order to permit the assembly to operate precisely even with
inaccuracies in the position or size of each individual
component.
All components which interact directly with the tips, nozzle, or
piston may be mounted to a single "shuttle assembly" and this
entire assembly may move as one piece. The shuttle assembly may
include a pipette body 6600 as shown in FIG. 23. The various
components may move with the shuttle assembly, which may be
distinguishable from traditional pipettes where only the nozzle
moves. This design may allow for simple, rigid connection of these
components to the critical piston/nozzle area without the need for
complex linkages or relative motion between several parts. It may
also provide an expandable "platform" upon which to integrate
future components and functionalities.
The piston may be housed in a cavity. The cavity where the piston
is housed may be cut from a single piece of metal and any valves or
nozzles may be mounted directly to this block. This may simplify
the mounting of components that may be directly involved in the
pipetting action and may provide a reliable air tight seal with
little unused volume. This may contribute to lower coefficients of
variation for pipetting. Any of the coefficient of variation values
described elsewhere herein may be achieved by the pipette.
The shuttle assembly may be intentionally underconstrained in
rotation about a shuttle guide rod. This may assist with tolerating
misalignment in the device as the shuttle may have sufficient
freedom to pivot side to side (e.g., xy plane) into whatever
position is needed to engage with tips or other interface
objects.
The components in the shuttle assembly may be encased in a two
piece "clamshell." Some, more than half, or all of the components
of the shuttle assembly may be encased within the clamshell. The
clamshell can include two symmetric halves to the shuttle chassis
that may hold the components in place. It can also include a single
half with deep pockets for component mounting and a flat second
half that completes the process of securing components in place.
The portions of the clamshell may or may not be symmetric, or may
or may not be the same thickness. These designs may allow the
assembly to include a large number of small components without a
complicated mounting method for each component. The clamshell
design may also allow for an assembly method where components can
be simply dropped into their correct position and then the second
half of the clamshell may be put in place and fastened, thus
locking everything in place. Additionally, this geometry lends
itself to an approach which integrates PCB routing boards directly
into the clamshell chassis components in order to facilitate wiring
for components inside the device.
Any description of clamshell may apply to a multi-part housing or
casing of the shuttle assembly. A housing of the shuttle assembly
may be formed from one, two, three, four, five, six, seven, eight
or more parts that may come together to form the housing. A
clamshell may be an example of a two-part shuttle housing. The
portions of a clamshell may or may not be connected by a hinge. The
portions of the clamshell may be separable from one another.
In some embodiments, each nozzle/tip/piston/shuttle assembly may be
combined into a single module (or blade) that is very thin and
flat. This may allow stacking of several blades at a set distance
from one another to create an arbitrarily large pipette. A desired
number of blades may be stacked together as needed, which may
permit the pipette to grow or shrink as needed. This modular
approach can provide great flexibility in the mechanical design
since it breaks up functionality and components into
interchangeable parts. It may also enable modular components in
this design to be rapidly adapted for and integrated into new
pipettor systems; thus the same basic modular components can be
capable of completing a large variety of tasks with different
requirements. The modularization of functionality may also enable
more efficient device protocols due to fast and independent nozzle
and piston control on board each pipette blade. This design may
provide advantages in servicing devices as defective blades can be
swapped individually, rather than necessitating an entirely new
pipettor. One or more of the blades may be independently movable
and/or removable relative to the other places.
FIG. 24C shows yet another embodiment wherein a plurality of
individual pipette units 6720 are provided. FIG. 24C is a front
view showing that each of the individual pipette units 6720 may be
individually movable relative to any other pipette unit in the
pipette chassis 6722. Some of the individual pipette units 6724 are
configured to be larger volume units and use larger head units
6726. Each of the pipette units 6720 and 6724 can be moved up and
down individually as indicated by arrow 6728. The system may
optionally have imaging devices 6730 and 6732 to view activity at
the pipette tips. This can be used as quality control to image
whether a tip is properly seated on the pipette nozzle, whether
sufficient volume of sample is in the tip, whether there is
undesired bubbles or other defects in the samples. In the present
embodiment, the plurality of imaging devices 6730 and 6732 are
sufficient to image all of the tips of the pipette nozzle.
FIG. 24D shows a side view of one embodiment an individual pipette
unit 6720. FIG. 24D shows that this pipette unit 6720 may have a
force-providing unit 6740 such as but not limited to a motor, a
piezoelectric drive unit, or the like. Although direct drive is not
excluded, the present embodiment uses a transmission such as but
not limited to pulleys, linkages, or gears 6744 and 6746 are used
to turn a lead screw 6748 that in turn moves the piston slide
mechanism 6750 which can move up and down as indicated by arrow
6752. This in turn moves a piston 6754 that drives, using direct or
air displacement, the aspiration or dispensing of fluid in tips
(not shown) coupled to the nozzle portion 6756. A tip ejector slide
6760 is actuated when the lower extending portion of the piston
slide mechanism 6750 pushes down on and moves the tip ejector slide
6760 down as indicated by arrow 6762. After the tip is ejected, the
slide 6760 may return to its original position.
As indicated by arrow 6770, the entire pipette unit 6720 can
translate up and down in a first frame of reference. Components
within the pipette unit 6720 can also move up and down in a second
frame of reference. The aspirating and dispensing of liquid is
independent of the movement of the unit 6720. The present
embodiment also shows that there is no tubing extending to an
external source. All fluid is kept separate from the internals of
the pipette unit 6720 so that the units can be used without having
to be cleaned or washed between uses. Some embodiments may have
hydrophobic coatings, seals, filters, filter paper, frits, septa,
or other fluid sealing items to prevent fluid and aerosolized
particles from entering the hardware, non-disposable portions of
the pipettes.
In some embodiments, fully modular pipette unit 6720 for various
fluid volumes and tip types can be provided with a common drive
train design. In one embodiment, nozzle and all fluid components
(including the piston/pump) are all located in a self-contained
module which can be built and validated outside the rest of the
assembly. The common platform allows for future versions of nozzles
with different functionality to be added to the system through
either new tips that can engage the heads or by replacing the
module pipette unit 6720 with an updated pipette unit, so long as
the interfaces both mechanical and electrical remain compatible
with what is on the pipette chassis.
Pipette units may be optimized to pipette different volumes of
fluid. Pipette units may have different volume capacities. In some
embodiments, the volume capacity of a pipette unit is related to
the volume of the piston block or piston, the nozzle of the pipette
unit, and/or tips which interface with the nozzle. In some
embodiments, a pipette unit may have a pipetting capacity as low as
0.1 microliter or as high as 20 mililiters, or any volume between.
In some embodiments, a pipette unit may be optimized for pipetting
a range of volumes, including, for example, 0.1-2 microliters;
0.1-10 microliters; 1-10 microliters; 1-50 microliters; 2-20
microliters; 1-100 microliters; 10-200 microliters; 20-200
microliters; or 100-1000 microliters.
Sensor Probes
In some embodiments, a pipette, pipette unit or any other component
of a device described herein may contain a probe. The probe may
include one or more sensors, e.g. for motion, pressure,
temperature, images, etc. Integration of a probe into one or more
components of a device may aid in monitoring one or more conditions
or events within a device. For example, a touch probe may be
integrated with a pipette, such that when a pipette is moved it may
sense its location (e.g. through pressure, motion, or imaging).
This may increase the precision and accuracy and lower the COV of
movement of the pipette. In another example, a probe on a pipette
may obtain information regarding the strength of a seal between a
pipette nozzle and a pipette tip. In another example, a probe may
contain a temperature sensor. If the probe is attached, for
example, to a centrifuge, cartridge, or pipette, the probe may
obtain information regarding the temperature of the area in the
vicinity of the centrifuge, cartridge, or pipette. A probe may be
in communication with a controller of a module, device, or system,
such that information obtained by the probe may be sent to the
controller. The controller may use this information in order to
calibrate or optimize device performance. For example, if a probe
senses that a tip is not properly sealed on a pipette nozzle, the
controller may direct the tip to be ejected from the pipette
nozzle, and for a new pipette tip to be loaded onto the nozzle. In
some embodiments, a probe may have a stand-alone structure, and not
be integrated with another component of a device.
Vessels/Tips
A system may comprise one, two or more vessels and/or tips, or may
contain a device that may comprise one, two or more vessels and/or
tips. One or more module of a device may comprise one, two or more
vessels and/or tips.
A vessel may have an interior surface and an exterior surface. A
vessel may have a first end and a second end. In some embodiments,
the first end and second ends may be opposing one another. The
first end or second end may be open. In some embodiments, a vessel
may have an open first end and a closed second end. In some
embodiments, the vessel may have one or more additional ends or
protruding portions which may be open or closed. In some
embodiments, a vessel may be used to contain a substrate for an
assay or reaction. In other embodiments, the substrate itself may
function as a sort of vessel, obviating the need for a separate
vessel.
The vessel may have any cross-sectional shape. For example, the
vessel may have a circular cross-sectional shape, elliptical
cross-sectional shape, triangular cross-sectional shape, square
cross-sectional shape, rectangular cross-sectional shape,
trapezoidal cross-sectional shape, pentagonal cross-sectional
shape, hexagonal cross-sectional shape, or octagonal
cross-sectional shape. The cross-sectional shape may remain the
same throughout the length of the vessel, or may vary.
The vessel may have any cross-sectional dimension (e.g., diameter,
width, or length). For example, the cross-sectional dimension may
be less than or equal to about 0.1 mm, 0.5 mm, 1 mm, 1.5 mm, 2 mm,
2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 1
cm, 1.2 cm, 1.5 cm, 2 cm, or 3 cm. The cross-sectional dimension
may refer to an inner dimension or an outer dimension of the
vessel. The cross-sectional dimension may remain the same
throughout the length of the vessel or may vary. For example, an
open first end may have a greater cross-sectional dimension than a
closed second end, or vice versa.
The vessel may have any height (wherein height may be a dimension
in a direction orthogonal to a cross-sectional dimension). For
example, the height may be less than or equal to about 0.1 mm, 0.5
mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm, 6
mm, 7 mm, 8 mm, 9 mm, 1 cm, 1.2 cm, 1.5 cm, 2 cm, 3 cm, 4 cm, 5 cm,
6 cm, 7 cm, 8 cm, 9 cm, or 10 cm. In some embodiments, the height
may be measured between the first and second ends of the
vessel.
The interior of the vessel may have a volume of about 1,000 .mu.L
or less, 500 .mu.L or less, 250 .mu.L or less, 200 .mu.L or less,
175 .mu.L or less, 150 .mu.L or less, 100 .mu.L or less, 80 .mu.L
or less, 70 .mu.L or less, 60 .mu.L or less, 50 .mu.L or less, 30
.mu.L or less, 20 .mu.L or less, 15 .mu.L or less, 10 .mu.L or
less, 8 .mu.L or less, 5 .mu.L or less, 1 .mu.L or less, 500 nL or
less, 300 nL or less, 100 nL or less, 50 nL or less, 10 nL or less,
1 nL or less, 500 pL or less, 250 pL or less, 100 pL or less, 50 pL
or less, 10 pL or less, 5 pL or less, or 1 pL or less.
One or more walls of the vessel may have the same thickness or
varying thicknesses along the height of the vessel. In some
instances, the thickness of the wall may be less than, and/or equal
to about 1 .mu.m, 3 .mu.m, 5 .mu.m, 10 .mu.m, 20 .mu.m, 30 .mu.m,
50 .mu.m, 75 .mu.m, 100 .mu.m, 200 .mu.m, 300 .mu.m, 400 .mu.m, 500
.mu.m, 600 .mu.m, 700 .mu.m, 800 .mu.m, 900 .mu.m, 1 mm, 1.5 mm, 2
mm, or 3 mm.
One or more vessels may be provided which may have the same shape
and/or size, or varying shapes and/or sizes.
A vessel may be formed of a single integral piece. Alternatively,
the vessel may be formed from two or more vessel pieces. The two or
more vessel pieces may be permanently attached to one another, or
may be selectively separable from one another. A vessel may include
a body and a cap. Alternatively, some vessels may only include a
body.
A vessel may be configured to contain and/or confine a sample. A
vessel may be configured to engage with a fluid handling system.
Any fluid handling system known in the art, such as a pipette, or
embodiments described elsewhere herein may be used. In some
embodiments, a vessel may be configured to engage with a tip that
may be connected to a fluid handling device, such as a pipette. A
vessel may be configured to accept at least a portion of a tip
within the vessel interior. A tip may be inserted at least partway
into the vessel. In some embodiments, the tip may be configured to
enter the vessel all the way to the bottom of the vessel.
Alternatively, the tip may be configured to be inserted no more
than part way into the vessel.
Vessel material can be of different types, depending on the
properties required by the respective processes. Materials may
include but not limited to: polymers, semiconductor materials,
metals, organic molecules, ceramics, composites, laminates, etc.
The material may be rigid or flexible, or able to transition
between the two. Vessel materials may include, but not limited to
polystyrene, polycarbonate, glass, metal, acrylics, semiconductor
materials, etc., and may include one of several types of coatings.
Vessel materials may be permeable to selective species by
introducing functionalized pores on the vessel walls. These allow
certain molecular species to pass through the material. Vessel
material can also be coated to prevent absorption of substances
such as water. Other coatings might be used to achieve specific
optical characteristics such as transmission, reflectance,
fluorescence, etc.
Vessel can be of different geometries including, but not limited
to, rectangular, cylindrical, hexagonal, and may include, without
limitation, attributes such as perforations, permeable membranes,
particulates or gels depending on the application. Vessels may be
comprised of microfluidic channels or electrical circuits,
optionally on a silicon substrate.
Vessels may also be active and perform a set of tasks. Vessels may
contain active transporters to pump fluids/suspensions through
membrane/septal barriers.
Vessels may be designed to have specific optical
properties--transparency, opacity, fluorescence, or other
properties related to any part of the electromagnetic spectrum.
Vessels may be designed to act as locally heated reactors by
designing the material to absorb strongly in the infrared part of
the electromagnetic spectrum.
Vessel walls might be designed to respond to different
electromagnetic radiation--either by absorption, scattering,
interference, etc. Combination of optical characteristics and
embedded sensors can result in vessels being able to act as
self-contained analyzers--e.g., photosensitive material on vessel
walls, with embedded sensors will transform a vessel into a
spectrophotometer, capable of measuring changes in optical
signals.
In some embodiments, vessels can be thought of as intelligent
containers which can change their properties by "sampling" the
surrounding fluids. Vessels could allow for preferential ion
transfer between units, similar to cells, signaled by electrical
and/or chemical triggers. They could also influence containment of
the fluid inside it in response to external and/or internal
stimuli. Response to stimuli may also result in change of
size/shape of the vessel. Vessels might be adaptive in response to
external or internal stimuli, and might enable reflex testing by
modification of assay dynamic range, signal strength, etc.
Vessels can also be embedded with different sensors or have
different sensors embedded in them, such as environmental
(temperature, humidity, etc.), optical, acoustic, or
electro-magnetic sensors. Vessels can be mounted with tiny wireless
cameras to instantly transmit information regarding its contents,
or alternatively, a process which happens in it. Alternatively, the
vessel can comprise another type of detector or detectors, which
transmit data wirelessly to a central processing unit.
Vessels can be designed for a range of different volumes ranging
from a few microliters to milliliters. Handling fluids across
different length and time scales involves manipulating and/or
utilizing various forces--hydrodynamic, inertial, gravity, surface
tension, electromagnetic, etc. Vessels may be designed to exploit
certain forces as opposed to others in order to manipulate fluids
in a specific way. Examples include use surface tension forces in
capillaries to transfer fluids. Operations such as mixing and
separation require different strategies depending on
volume--vessels may be designed to specifically take advantage of
certain forces. Mixing, in particular is important while handling
small volumes, since inertial forces are absent. Novel mixing
strategies such as using magnetic particles with external forcing,
shear-induced mixing, etc. might be adopted to achieve efficient
mixing.
Vessels offer flexibility over microfluidic chips due to their
inherent flexibility in handling both small and large volumes of
fluids. Intelligent design of these vessels allows us to handle a
larger range of volumes/sizes compared to microfluidic devices. In
one embodiment, vessels were designed with tapered bottoms. This
taper is in at least the interior surface of the vessel. It should
be understood that the exterior may be tapered, squared, or
otherwise shaped so long as the interior is tapered. These features
reduce sample/liquid overages that are needed. Namely, small
volumes can be mixed in the vessel and extracted without
wasting/leaving behind residual liquid. This design allows one to
work with both small volumes and larger volumes of liquids. In
addition, vessels can take advantage of forces which microfluidic
devices cannot--thereby offering more flexibility in processing.
Vessels may also offer the ability to dynamically change scales, by
switching to different sizes. In the "smart vessel" concept, the
same vessel can change capacity and other physical attributes to
take advantage of different forces for processing fluids. This
actuation can be programmed, and externally actuated, or initiated
by changes in fluid inside.
The functionality of a vessel can go beyond fluid
containment--different vessels can communicate via surface features
or external actuation and engage in transport of fluids/species
across vessel boundaries. The vessel thus becomes a vehicle for
fluid containment, processing, and transport--similar to cells.
Vessels can fuse in response to external actuation and/or changes
in internal fluid composition. In this embodiment, vessels can be
viewed as functional units, capable of executing on or several
specialized function--separations such as isoelectric focusing,
dialysis, etc. Vessels can be used to sample certain fluids and
generate information regarding transformations, end points,
etc.
Vessels can act as self-contained analytical units, with in-built
detectors and information exchange mechanisms, through sensors and
transmitters embedded inside vessel walls. Vessel walls can be made
with traditional and/or organic semiconductor materials. Vessels
can be integrated with other sensors/actuators, and interface with
other vessels. A vessel, in this embodiment, can be viewed as a
system capable of containment, processing, measurement, and
communication. In some embodiments, a vessel may contain a chip for
electric manipulation of very small volumes of liquid.
Vessels can also have sample extraction, collection, and fluid
transfer functionalities. In this embodiment, a vessel would act
like a pipette being stored in the cartridge, and able to transfer
fluid to a specific location. Examples include a viral transport
medium for nucleic acid amplification assays, where the vessel is
used to both collect and transport the viral transport medium.
Another example would be a cuvette coming out of the device in
order to collect a fingerstick sample.
Vessels may be designed to contain/process various sample types
including, but not limited to blood, urine, feces, etc. Different
sample types might require changes in vessel
characteristics--materials, shape, size, etc. In some embodiments,
vessels perform sample collection, processing, and analysis of
contained sample.
A vessel or subvessel may be sealed with or otherwise contain
reagents inside it. A pipette may act to release the reagent from
the vessel when needed for a chemical reaction or other process,
such as by breaking the seal that contains the reagent. The vessels
may be composed of glass or other material. A reagent that would
otherwise be absorbed into traditional polymer tips or degrade when
exposed to the environment may necessitate such
compartmentalization or sealing in a vessel.
In some embodiments, vessels provided herein may have rounded edges
to minimize fluid loss during fluid handling.
A vessel (e.g. a tip) may have an interior surface and an exterior
surface. A vessel (e.g. a tip) may have a first end and a second
end. In some embodiments, the first end and the second ends may be
opposing one another. The first end and/or second end may be open.
A vessel (e.g. a tip) may include a passageway connecting the first
and second ends. In some embodiments, a vessel (e.g. a tip) may
include one or more additional ends or protrusions. For example,
the vessel (e.g. a tip) may have a third end, fourth end, or fifth
end. In some embodiments, the one or more additional ends may be
open or closed, or any combination thereof.
The vessel (e.g. a tip) may have any cross-sectional shape. For
example, the vessel may have a circular cross-sectional shape,
elliptical cross-sectional shape, triangular cross-sectional shape,
square cross-sectional shape, rectangular cross-sectional shape,
trapezoidal cross-sectional shape, pentagonal cross-sectional
shape, hexagonal cross-sectional shape, or octagonal
cross-sectional shape. The cross-sectional shape may remain the
same throughout the length of the vessel (e.g. a tip), or may
vary.
The vessel (e.g. a tip) may have any cross-sectional dimension
(e.g., diameter, width, or length). For example, the
cross-sectional dimension may be less than or equal to about 0.1
mm, 0.5 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm,
5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 1 cm, 1.2 cm, 1.5 cm, 2 cm, or 3 cm.
The cross-sectional dimension may refer to an inner dimension or an
outer dimension of the vessel (e.g. a tip). The cross-sectional
dimension may remain the same throughout the length of the vessel
(e.g. a tip) or may vary. For example, an open first end may have a
greater cross-sectional dimension than an open second end, or vice
versa. The cross-sectional dimension ratio of the first end to the
second end may be less than, and/or equal to about 100:1, 50:1,
20:1, 10:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:10,
1:20, 1:50 or 1:100. In some embodiments, the change in the
cross-sectional dimension may vary at different rates.
The vessel (e.g. a tip) may have any height (wherein height may be
a dimension in a direction orthogonal to a cross-sectional
dimension). For example, the height may be less than, or equal to
about 0.1 mm, 0.5 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4
mm, 4.5 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 1 cm, 1.2 cm, 1.5 cm, 2
cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, or 10 cm. In some
embodiments, the height may be measured between the first and
second ends of the tip.
The interior of the vessel (e.g. a tip) may have a volume of about
1,000 .mu.L or less, 500 .mu.L or less, 250 .mu.L or less, 200
.mu.L or less, 175 .mu.L or less, 150 .mu.L or less, 100 .mu.L or
less, 80 .mu.L or less, 70 .mu.L or less, 60 .mu.L or less, 50
.mu.L or less, 30 .mu.L or less, 20 .mu.L or less, 15 .mu.L or
less, 10 .mu.L or less, 8 .mu.L or less, 5 .mu.L or less, 1 .mu.L
or less, 500 nL or less, 300 nL or less, 100 nL or less, 50 nL or
less, 10 nL or less, 1 nL or less, 500 pL or less, 250 pL or less,
100 pL or less, 50 pL or less, 10 pL or less, 5 pL or less, or 1 pL
or less.
One or more walls of the vessel (e.g. a tip) may have the same
thickness or varying thicknesses along the height of the vessel
(e.g. a tip). In some instances, the thickness of the wall may be
less than and/or equal to about 1 .mu.m, 3 .mu.m, 5 .mu.m, 10
.mu.m, 20 .mu.m, 30 .mu.m, 50 .mu.m, 75 .mu.m, 100 .mu.m, 200
.mu.m, 300 .mu.m, 400 .mu.m, 500 .mu.m, 600 .mu.m, 700 .mu.m, 800
.mu.m, 900 .mu.m, 1 mm, 1.5 mm, 2 mm, or 3 mm.
One or more vessels (e.g. a tip) may be provided which may have the
same shape and/or size, or varying shapes and/or sizes. Any of the
various embodiments described herein may have one or more features
of the vessels and/or tips as described elsewhere herein.
A tip may be formed of a single integral piece. Alternatively, the
tip may be formed from two or more tip pieces. The two or more tip
pieces may be permanently attached to one another, or may be
selectively separable from one another. Chemistries or sensors may
also be physically integrated into a tip, effectively enabling a
complete laboratory test on a vessel (e.g. a tip). Vessels (e.g. a
tip) may each individually serve different preparatory, assay, or
detection functions. Vessels (e.g. a tip) may serve multiple
functions or all functions within a single vessel or tip.
A vessel (e.g. a tip) may be formed of a material that may be
rigid, semi-rigid, or flexible. The vessel (e.g. a tip) may be
formed of material that is conductive, insulating, or that
incorporates embedded materials/chemicals/etc. The vessel (e.g. a
tip) may be formed of the same material or of different
materials.
In some embodiments, the vessel (e.g. a tip) may be formed of a
transparent, translucent, or opaque material.
The inside surface of a tip can be coated with reactants that are
released into fluids; such reactants can be plated, lyophilized,
etc. The vessel (e.g. a tip) may be formed of a material that may
permit a detection unit to detect one or more signals relating to a
sample or other fluid within the vessel (e.g. a tip). For example,
the vessel (e.g. a tip) may be formed of a material that may permit
one or more electromagnetic wavelength to pass therethrough.
Examples of such electromagnetic wavelengths may include visible
light, IR, far-IR, UV, or any other wavelength along the
electromagnetic spectrum. The material may permit a selected
wavelength or range(s) of wavelengths to pass through. Examples of
wavelengths are provided elsewhere herein. The vessel (e.g. a tip)
may be transparent to permit optical detection of the sample or
other fluid contained therein.
The vessel (e.g. a tip) may form a wave guide. The vessel (e.g. a
tip) may permit light to pass through perpendicularly. The vessel
(e.g. a tip) may permit light to pass through along the length of
the vessel. The vessel (e.g. a tip) may permit light to light to
enter and/or travel at any angle. In some embodiments, the vessel
(e.g. a tip) may permit light to enter and/or travel at selected
angles or ranges of angles. The vessel and/or tip may form one or
more optic that may focus, collimate, and/or disperse light.
The material may be selected to be impermeable to one or more
fluids. For example, the material may be impermeable to the sample,
and/or reagents. The material may be selectively permeable. For
example, the material may permit the passage of air or other
selected fluids.
Examples of materials used to form the vessel and/or tip may
include functionalized glass, Si, Ge, GaAs, GaP, SiO.sub.2,
SiN.sub.4, modified silicon, or any one of a wide variety of gels
or polymers such as (poly)tetrafluoroethylene,
(poly)vinylidenedifluoride, polystyrene, polycarbonate,
polypropylene, polymethylmethacrylate (PMMA), ABS, or combinations
thereof. In an embodiment, an assay unit may comprise polystyrene.
The materials may include any form of plastic, or acrylic. The
materials may be silicon-based. Other appropriate materials may be
used in accordance with the present invention. Any of the materials
described here, such as those applying to tips and/or vessels may
be used to form an assay unit. A transparent reaction site may be
advantageous. In addition, in the case where there is an optically
transmissive window permitting light to reach an optical detector,
the surface may be advantageously opaque and/or preferentially
light scattering.
Vessels and/or tips may have the ability to sense the liquid level
therein. For example, vessels and/or tips may have capacitive
sensors or pressure gauges. The vessels may employ any other
technique known in the art for detecting a fluid level within a
container. The vessels and/or tips may be able to sense the liquid
level to a high degree of precision. For example, the vessel and/or
tip may be able to detect a liquid level to within about 1 nm, 5
nm, 10 nm, 50 nm, 100 nm, 150 nm, 300 nm, 500 nm, 750 nm, 1 .mu.m,
3 .mu.m, 5 .mu.m, 10 .mu.m, 50 .mu.m, 75 .mu.m, 100 .mu.m, 150
.mu.m, 200 .mu.m, 300.mu.m, 400 .mu.m, 500.mu.m, 600 .mu.m, 700
.mu.m, 800 .mu.m, 900 .mu.m, or 1 mm.
A tip may assist with the dispensing and/or aspiration of a sample.
A tip may be configured to selectively contain and/or confine a
sample. A tip may be configured to engage with a fluid handling
device.
Any fluid handling system known in the art, such as a pipette, or
embodiments described elsewhere herein may be used. The tip may be
connected to the fluid handling device to form a fluid-tight seal.
In some embodiments, the tip may be inserted into a vessel. The tip
may be inserted at least partway into the vessel.
The tip may include a surface shape or feature that may determine
how far the tip can be inserted into the vessel.
Vessels and/or tips may be independently formed and may be separate
from one another. Vessels and/or tips may be independently movable
relative to one another. Alternatively, two or more vessels and/or
tips may be connected to one another. They may share a common
support. For example, the two or more vessels and/or tips may be
cut from a same material--e.g., cut into a common substrate. In
another example, two or more vessels and/or tips may be directly
linked adjacent to one another so that they directly contact one
another. In another example, one or more linking component may link
the two or more vessels and/or tips together. Examples of linking
components may include bars, strips, chains, loops, springs,
sheets, or blocks. Linked vessels and/or tips may form a strip,
array, curve, circle, honeycombs, staggered rows, or any other
configuration. The vessels and/or connections may be formed of an
optically transparent, translucent, and/or opaque material. In some
instances, the material may prevent light from entering a space
within the vessels and/or cavities. Any discussion herein of
vessels and/or tips may apply to cuvettes and vice versa.
Cuvettes may be a type of vessel.
FIG. 26 provides an example of a vessel strip. The vessel strip
provides an example of a plurality of vessels that may be commonly
linked. The vessel strip 6900 may have one or more cavities 6910.
The cavities may accept a sample, fluid or other substance directly
therein, or may accept a vessel and/or tip that may be configured
to confine or accept a sample, fluid, or other substance therein.
The cavities may form a row, array, or any other arrangement as
described elsewhere herein. The cavities may be connected to one
another via the vessel strip body.
The vessel strip may include one or more pick-up interface 6920.
The pick-up interface may engage with a sample handling apparatus,
such as a fluid handling apparatus. The pick-up interface may
interface with one or more pipette nozzle. Any of the interface
configurations described elsewhere herein may be used.
For example, a pipette nozzle may be press-fit into the pick-up
interface. Alternatively, the pick-up interface may interface with
one or more other component of the pipette.
The vessel strip may be useful for colorimetric analysis or
cytometry. The vessel strip may be useful for any other analysis
described elsewhere herein.
FIGS. 27A and 27B provide another example of a cuvette 7000. The
cuvette provides an example of a plurality of channels that may be
commonly linked. The cuvette carrier may have a body formed from
one, two or more pieces. In one example, a cuvette may have a top
body portion 7002a, and a bottom body portion 7002b. The top body
portion may have one or more surface feature thereon, such as a
cavity, channel, groove, passageway, hole, depression, or any other
surface feature. The bottom body portion need not include any
surface features. The bottom body portion may be a solid portion
without cavities. The top and bottom body portion may come together
to form a cuvette body. The top and bottom body portion may have
the same footprint, or may have differing footprints. In some
instances, the top body portion may be thicker than the bottom body
portion. Alternatively, the bottom body portion may be thicker or
equal in thickness to the top body portion.
The cuvette 7000 may have one or more cavities 7004. The cavities
may accept a sample, fluid or other substance directly therein. The
cavities may form a row, array, or any other arrangement as
described elsewhere herein. The cavities may be connected to one
another via the cuvette body. In some instances, the bottom of a
cavity may be formed by a bottom body portion 7002b. The walls of a
cavity may be formed by a top body portion 7002a.
The cuvette may also include one or more fluidically connected
cavities 7006. The cavities may accept a sample, fluid or other
substance directly therein, or may accept a vessel and/or tip
(e.g., cuvette) that may be configured to confine or accept a
sample, fluid, or other substance therein. The cavities may form a
row, array, or any other arrangement as described elsewhere herein.
The cavities may be fluidically connected to one another via a
passageway 7008 through the cuvette body.
The passageway 7008 may connect two cavities, three cavities, four
cavities, five cavities, six cavities, seven cavities, eight
cavities, or more. In some embodiments, a plurality of passageways
may be provided. In some instances, a portion of the passageway may
be formed by a top body portion 7002a, and a portion of the
passageway may be formed by a bottom body portion 7002b. The
passageway may be oriented in a direction that is not parallel
(e.g., is parallel) to an orientation of a cavity 7006 to which it
connects. For example, the passageway may be horizontally oriented
while a cavity may be vertically oriented. The passageway may
optionally permit a fluid to flow from one fluidically connected
cavity to another.
The cuvette may include one or more pick-up interface. Optionally,
a pick-up interface may be one or more cavity, 7004, 7006 of the
cuvette. The pick-up interface may engage with a sample handling
apparatus, such as a fluid handling apparatus. The pick-up
interface may interface with one or more pipette nozzle. Any of the
interface configurations described elsewhere herein may be used.
For example, a pipette nozzle may be press-fit into the pick-up
interface, or the nozzle may interact magnetically with the pick-up
interface. Alternatively, the pick-up interface may interface with
one or more other component of the pipette.
Optionally, the cuvette may include embedded magnet(s) or magnetic
feature(s) that allow for a sample handling apparatus to pickup
and/or dropoff the cuvette based on magnetic forces. In some
embodiments, a sample handling apparatus may directly transfer a
cuvette from a cartridge to a cytometry station. In some
embodiments, a module-level sample handling system may transfer a
cuvette from an assay station to a cytometry station or detection
station in the same module. In some embodiments, a device-level
sample handling system may transfer a cuvette from an assay station
to a cytometry station or detection station in a different
module.
Cuvettes may be useful, for example, for colorimetric analysis or
cytometry. The cuvette may be useful for any other analysis
described elsewhere herein. In some embodiments, a cuvette has a
configuration optimized for use with a cytometer, e.g. to interface
with a microscopy stage. In some embodiments, a cuvette has a
configuration optimized for use with a spectrophotometer.
A cuvette may be formed of any material, including those described
elsewhere herein. The cuvette may optionally be formed of a
transparent, translucent, opaque material, or any combination
thereof. The cuvette may prevent a chemical contained therein from
passing from one cavity to another.
FIG. 28 shows an example of a tip in accordance with an embodiment
of the invention. The tip 7100 may be capable of interfacing with a
microcard, cuvette carrier and/or strip, including any examples
described herein.
The tip may include a narrow portion that may deposit a sample
7102, a sample volume area 7104, and/or a nozzle insertion area
7106. In some instances, the tip may include one or more of the
areas described. The sample deposit area may have a smaller
diameter than a sample volume area. The sample volume area may have
a smaller volume than a nozzle insertion area. The sample deposit
area may have a smaller volume than a nozzle insertion area.
In some embodiments, a lip 7108 or surface may be provided at an
end of the nozzle insertion area 7106. The lip may protrude from
the surface of the nozzle insertion area.
The tip may include one or more connecting region, such as a funnel
region 7110 or step region 7112 that may be provided between
various types of area. For example, a funnel region may be provided
between a sample deposit area 7102 and a sample volume area 7104. A
step region 7112 may be provided between a sample volume area 7104,
and a nozzle insertion area. Any type of connecting region may or
may not be provided between the connecting regions.
A sample deposit area may include an opening through which a fluid
may be aspirated and/or dispensed. A nozzle insertion area may
include an opening into which a pipette nozzle may optionally be
inserted. Any type of nozzle-tip interface as described elsewhere
herein may be used. The opening of the nozzle insertion area may
have a greater diameter than an opening of the sample deposit
area.
The tip may be formed of a transparent, translucent, and/or opaque
material. The tip may be formed from a rigid or semi-rigid
material. The tip may be formed from any material described
elsewhere herein.
The tip may or may not be coated with one or more reagents.
The tip may be used for nucleic acid tests, or any other tests,
assays, and/or processes described elsewhere herein.
FIG. 29 provides an example of a test strip. The test strip may
include a test strip body 7200. The test strip body may be formed
from a solid material or may be formed from a hollow shell, or any
other configuration.
The test strip may include one or more cavities 7210. In some
embodiments, the cavities may be provided as a row in the body. The
cavities may optionally be provided in a straight row, in an array
(e.g., m.times.n array where m, n are whole numbers greater than
zero including but not limited to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, or more). The cavities may be positioned in
staggered rows, concentric circles, or any other arrangement.
The cavities may accept a sample, fluid or other substance directly
therein, or may accept a vessel and/or tip that may be configured
to confine or accept a sample, fluid, or other substance therein.
The cavities may be configured to accept a tip, such as a tip
illustrated in FIG. 28, or any other tip and/or vessel described
elsewhere herein. The test strip may optionally be a nucleic acid
test strip, which may be configured to accept and support nucleic
acid tips.
A cavity may have a tapered opening. In one example, a cavity may
include a top portion 7210a, and a bottom portion 7210b. The top
portion may be tapered and may have an opening greater in diameter
than the bottom portion.
In some embodiments, the cavity may be configured to accept a
pipette nozzle for pick-up. One or more pipette nozzle may engage
with one or more cavity of the test strip. One, two, three, four,
five, six or more pipette nozzles may simultaneously engage with
corresponding cavities of the test strip. A tapered opening of the
cavity may be useful for nozzle pick-up. The pipette nozzle may be
press-fit into the cavity or may interface with the cavity in any
other manner described herein.
One or more sample and/or reagent may be provided in a test strip.
The test strips may have a narrow profile. A plurality of test
strips may be positioned adjacent to one another. In some
instances, a plurality of test strips adjacent to one another may
form an array of cavities. The test strips may be swapped out for
modular configurations. The test strips and/or reagents may be
movable independently of one another. The test strips may have
different samples therein, which may need to be kept at different
conditions and/or shuttled to different parts of the device on
different schedules.
FIG. 30 shows another example of a test strip. The test strip may
have a body 7300. The body may be formed from a single integral
piece or multiple pieces. The body may have a molded shape. The
body may form a plurality of circular pieces 7310a, 7310b connected
to one another, or various shapes connected to one another. The
bodies of the circular pieces may directly connect to one another
or one or more strip or space may be provided between the
bodies.
The test strip may include one or more cavities 7330. In some
embodiments, the cavities may be provided as a row in the body. The
cavities may optionally be provided in a straight row, in an array
(e.g., m.times.n array where m, n are whole numbers greater than
zero including but not limited to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, or more). The cavities may be positioned in
staggered rows, concentric circles, or any other arrangement.
The cavities may accept a sample, fluid or other substance directly
therein, or may accept a vessel and/or tip that may be configured
to confine or accept a sample, fluid, or other substance therein.
The cavities may be configured to accept a tip, such as a tip
illustrated in FIG. 28, or any other tip and/or vessel described
elsewhere herein. The test strip may optionally be a nucleic acid
test strip, which may be configured to accept and support nucleic
acid tips.
The test strip body 7330 may be molded around the cavities 7330.
For example, if a cavity has a circular cross-section, the test
strip body portion 7310a, 7310b around that cavity may have a
circular cross-section. Alternatively, the test strip body need not
match the cavity shape.
In some embodiments, the test strip may include an external pick-up
receptacle 7320. One or more pipette nozzle may engage with one or
more external pick-up receptacle of the test strip. One, two,
three, four, five, six or more pipette nozzles may simultaneously
engage with corresponding pick-up receptacles of the test strip. A
pick-up receptacle may have one or more cavity 7340 or through-hole
that may be capable of interfacing with a pipette nozzle. The
pipette nozzle may be press-fit into the cavity or may interface
with the receptacle in any other manner described herein.
One or more samples and/or reagents may be provided in a test
strip. The one or more sample may be directly within a cavity or
may be provided in tips and/or vessels that may be placed in a
cavity of the test strip. The test strips may have a narrow
profile. A plurality of test strips may be positioned adjacent to
one another. In some instances, a plurality of test strips adjacent
to one another may form an array of cavities.
The test strips may be swapped out for modular configurations. The
test strips may be movable independently of one another. The test
strips and/or reagents may have different samples therein, which
may need to be kept at different conditions and/or shuttled to
different parts of the device on different schedules.
In embodiments, a sample handling device may contain a fluid
handling apparatus. The fluid handling apparatus may have both low
volume (1-10 uL capacity) and high volume (10-50 uL capacity)
nozzles, to ensure high volumetric precision at low volumes. The
narrow volumetric range of the low volume nozzles allows for a
small piston cross section, resulting in a large stroke length for
small volumes. This ensures high-precision low-volume handling.
In embodiments, all nozzle z-movements and aspiration/dispense
steps of a fluid handling apparatus are independently actuated and
controlled, allowing each drive train to be individually
personalized and optimized. This ensures precise positioning and
fluid handling.
In embodiments, the pistons in the fluid handling apparatus are
designed to minimize dead volume in the air column. This may be
achieved by minimizing the volume of air column in the nozzle, and
minimizing distance between the piston assembly and the nozzle.
This results in precise transfer of pressure between the piston and
the nozzle, and positively impacts precision.
In embodiments, the fluid handling apparatus is designed with
high-resolution encoders and low-backlash drive train to enable
small, precise, movements. This may be accomplished by selecting
fine-pitched gears and lead-screws, and high-resolution encoders on
all drive trains. The high precision for small movements in the
drive train directly translate to high precision fluid handling at
small volumes
Piston assemblies of a fluid handling apparatus may be constructed
with wear-resistant, low-friction seals between the plunger and the
piston chamber. This results in a consistent seal over the life of
the sample handling device, ensuring precise fluid handling.
The taper-taper interface between the pipette nozzles of a fluid
handling apparatus and consumable parts ensure a robust seal and
are designed with high tolerance features to enable repeatable
seals and performance across nozzles, tips, and devices.
During pick-up of a consumable (tip or vessel) by the fluid
handling apparatus, seal between nozzle and consumable may be
achieved by applying a constant downward force, which results in
the consumable being pressed by the nozzle against the rigid
surface of the cartridge. This force is responsible for creating
the seal between the nozzle and the consumable. Precise control of
this force in a device ensures that the seal is always consistent.
This seal consistency directly impacts volumetric precision.
The structure of a sample handling device may be designed to be
rigid to minimize slop. This, in addition to the high-resolution,
low-backlash drivetrain, and closed-loop control, allow for very
precise movements and positioning. This ensures consistency across
consumable pickup, and interaction between tips and vessels. This
positional precision directly impacts the ability to handle small
volume fluids in small vessels. In addition to the rigid structure,
each sample handling device may be individually personalized on a
Co-ordinate Measuring Machine (CMM) to ensure that the location of
each resource in a sample handling device is accurately
calibrated.
In embodiments, a sample handling device may have active
temperature control, which maintains the temperature inside sample
handling device to within +/-1 C of target temperature. This may
maintains a constant temperature in the piston assembly of the
fluid handling apparatus. This minimizes pressure variations in the
piston air column, and positively impacts volumetric precision.
In embodiments, tips for use with a fluid handling apparatus of a
sample handling device may be designed with a gradual taper,
avoiding any sharp angles, which may retain drops of fluid. This
minimizes errors at small volume transfers. In addition, certain
tips are coated with Surfasil, which makes the tip surface
hydrophobic, preventing any fluid retention on the outer surface of
tips.
In embodiments, pipette nozzles may be made from metal (aluminum)
while single-use consumables are made of plastic polymers. Use of
these materials in these mating parts may ensure long life and
robust performance of a sample handling device over time.
In embodiments, consumables for use with a sample handling device
are single use ensuring that they do not fatigue or deform.
In embodiments, tip and vessel geometry for use with devices and
systems provided herein are designed to minimize overflow when a
tip is inserted into a fluid-filled vessel. Surfasil coating on the
certain vessels (in addition to tips) prevents capillary driven
fluid flow between the tip outer surface and the vessel inner
surface. These measures also prevent fluid retention on the outside
of tips.
In embodiments, vessel bottoms may have a conical geometry to
minimize overage, allowing for maximum recovery of fluid from a
vessel. This allows systems and devices provided herein to operate
with very small overages, minimizing sample waste.
In embodiments, all consumables for use with systems and devices
provided herein may be fabricated in a manufacturing facility held
to high tolerances with frequent and rigid inspection. This ensures
that all consumable types are precisely dimensioned, allowing for
high precision in interactions between the fluid handling module
and the consumables.
In embodiments, in systems and devices provided herein, fluid
handling (aspiration, dispense, mix) is optimized to the physical
properties of the fluid being handled. For example, fluids with
high viscosity or low surface tension are aspirated and dispensed
at slow speeds, to minimize adverse fluidic effects and to ensure
accurate volumetric transfer. In addition to speed, forward and
reverse pipetting is used depending on fluid type. A fluid handling
apparatus may also have different calibrations based on fluid type
to ensure volumetric accuracy for all fluid types.
In embodiments, precise positioning of nozzle z-positioning and
tightly tolerance consumables enable the offset between the tip and
the fluid level in a vessel to be highly precise. This may be
accomplished by tracking the volume.
In embodiments, devices and systems provided herein may be designed
for function in a point of service location. Such locations may be
outside of a traditional laboratory, and may be for example, in a
retail or home location.
In embodiments, such devices or systems may have various qualities,
such as: 1) Not requiring in-field user calibration; 2) quality
control may be run on-board cartridges to ensure proper device
sample processing without any user intervention; 3) the device or
system may be designed for sustained operation for 24 hours, 7 days
a week, for over 1 year without failure.
Systems and devices provided herein may incorporate several robust
design elements.
In embodiments, systems and devices provided herein may be
developed according to design control procedures that ensure that
function requirements are documented and validated. Systems and
methods may be designed for reliability, in which one or more of
the following are met: a) each design element in the system or
device was evaluated for robustness incorporating several orders of
factors of safety to ensure that the functional requirements are
satisfied; b) minimal and simplified user interactions with the
system or device; c) monitoring of system performance via
integrated highly precise and accurate sensors and encoders; d)
intelligent integrated feedback and controls that ensure robust
performance over the life of the system or device; e) selection of
very reliable components for the system of device in order to meet
requirements--examples include: brushless motors for long life,
durable and stiff materials that will not fatigue, high quality
bearings and wear pairings to provide extended life and
performance, and rigid structures; and f) extensive testing of
system and components to demonstrate and validate performance.
In embodiments, systems and devices provided herein may be designed
with risk assessment procedures, such that risk management, hazard
analysis, FMEA procedures are followed to evaluate system and
process performance and highlight elements that may need
mitigation.
In embodiments, systems and devices provided herein may be designed
with quality control and quality assurance, such that effective QC
and QA procedures are established to ensure the highest quality
systems are designed and produced.
In embodiments, systems and devices provided herein may be designed
with good manufacturing procedures, such that production processes
follow good manufacturing principles to ensure high quality systems
are produced.
In embodiments, systems and devices provided herein may incorporate
one or more features for error detection during sample
handling.
For example, during pre-analytical steps, time of collection may be
recorded by scanning the vessel containing a sample after
collection of the sample. The time of sample run is recorded by the
system or device during scanning of a barcode on a cartridge for
sample processing. This time information may be sent to an
automated laboratory computer system, which flags an error if the
time interval between sample collection and run exceeds specified
interval.
Systems and devices may include real time monitoring of liquid
handling system and associated motion via very fine resolution
encoders and sensors. If any movement is outside of pre-defined
tolerances one or more actions may occur, such as: a) the system or
device may terminate the protocol depending on the error detected;
b) the system or device may auto-correct to bring itself into
tolerance and continue with the protocol; c) the system or device
will send an error message to a laboratory computer system with the
log file for evaluation.
Systems and devices provided herein may include monitoring of
resource pickup and drop off by the liquid handling system. For
example, images may be taken in a camera module of vessel
pickup/drop-off operations, and images are transmitted to a
laboratory computer system, where images are automatically
processed to determine errors in real time.
Systems and devices provided herein may include features for
monitoring liquid handling errors. For example, pipette tips may be
imaged in a camera module after aspiration/dispense and images are
sent to a laboratory computer system, where image processing
algorithms automatically detect out of specification operations.
For cytometry assays, the absolute number of control beads in a
channel may be counted in the computer system, and the system or
device is flagged for error if the total number lies beyond a
specified range. For general chemistry assays, the intensity value
at 800 nm is compared in the computer system against a minimum and
maximum intensity value, and the system or device is flagged if the
value is beyond acceptable range.
Systems and devices provided herein may include features for
monitoring detector errors. For example, for a cytometer,
fluorescent beads may be included as part of the reagent in
cytometry assays. The fluorescence intensity from these beads are
compared against an accepted range in the computer system to check
for inconsistencies. In another example, for a spectrophotometer:
Intensity at 800 nm is compared against an accepted range in the
computer system to check for errors. In another example, for a
luminometer: Dark counts are compared against an accepted range in
the computer system to check for errors. In another example, for
nucleic acid amplification assays, fluorescence intensity counts
are compared with and without the sample (blank) against an
accepted range in the computer system to check for errors.
Systems and devices provided herein may have on-board controls.
On-board controls are used to check the performance of the system
including: liquid handling, reagent activity, detector performance,
environmental control, data transmission, calibration, and data
processing. For ELISA and GC assays, the sequence of runs follows
control-sample-control to ensure that control runs are fully
representative of system performance.
Systems and devices provided herein may monitor sample/matrix
related errors. For example, after aspiration into tips, whole
blood and plasma sample volumes are imaged in the camera module and
images are sent to the computer system, where image processing
algorithms automatically calculate the sample volume. Short samples
are flagged by the computer system and the protocol is terminated
by the system or device accordingly. For general chemistry or ELISA
assays: Absorbance spectrum for sample blank is analyzed in the
computer system to detect hemolysis, lipemia, or icterus. All
absorbance spectra are scanned for spurious peaks, and flagged as
errors by the computer system. For cytometry assays: Scattergram
and cells/field of view are used as metrics to determine sample
related errors in the computer system.
It should be understood that measures may be implemented to
minimize cross-contamination in the systems and methods herein,
which is desirable particularly when handling microliter volumes of
sample.
In one non-limiting example, fluid handling disposables such as but
not limited to fluid handling tips, pipette tips, or other fluid
contacting workpiece are used in a workflow wherein the fluid
contacting workpiece(s) are not used across more than one assay.
Optionally, fluid contacting workpiece(s) are not used to interact
with more than one fluid well or vessel. Optionally, fluid
contacting workpiece(s) are not used to interact with more than two
fluid well or vessel. Optionally, fluid contacting workpiece(s)
used for transferring reagent are not dipped in a sample/dilution
well, unless there is only one assay in the cartridge which uses
the particular sample/dilution well. Optionally, fluid contacting
workpiece(s) which have been used for transferring sample of one
dilution do not come in contact with sample of any other
dilution.
It should be understood that fluid remaining in any fluid
contacting workpiece is disposed of directly into an absorbent
touch-off pad, ensuring that fluid is removed from the tip and is
contained in the absorbent pad and not free to mix with other
reagents. Optionally, touch-off points are separated such that
fluid dispensed into one touch-off point, such as but not limited a
touch-off point on the absorbent touch-off pad, does not flow to an
adjacent future touch-off point.
High positional precision and control on gantry (x,y axes), and the
liquid handling module (z and pump axes) are used in one or more
embodiments to ensure that fluid operations (aspiration, dispense,
mixing) can be done without fluid overflowing in tips and vessels.
In this manner, the fluid control within the fluid contacting
workpiece is controlled with a pre-selected, known precision. Fluid
contacting workpiece(s) and vessels are also designed to minimize
chances for overflow by having sufficient dead space.
Optionally, tips or fluid contacting workpieces may have filters at
one or more locations within the tip or fluid contacting workpieces
to prevent fluid contact with nozzles. This can be desirable as the
fluid contacting workpieces are disposable items and the nozzles
are hardware items that may interact with a plurality of tips while
the aliquots of sample from the same subject are being processed.
This minimizes cross contamination when unused fluid contacting
workpieces are coupled to hardware such as but not limited to the
nozzle that may interact with a plurality of disposable without a
cleaning step or a plurality of cleaning steps.
Optionally, a thermal control system is designed to eliminate low
pressure zones, which ensures that there is no downward force
acting on the fluid inside tips. These low pressure zones may be in
the environment within the system but external to the tip, where
such low pressure zones may cause handling issues for fluid inside
the tips or workpieces.
It should be understood that high gantry precision and optimized
tip pick-up protocol may be used to ensure a good, consistent seal
between the nozzle and the tip, which maintains a holding force on
the fluid column in the tip, minimizing chances of fluid leakage.
By way of non-limiting example, a protocol may involve verifying
visually, by touch, or both that a tip is fully seated onto a
nozzle. Optionally, some embodiments may press the tip onto the
fluid handling nozzle two or more times to increase the likelihood
that at least one of those steps will have properly seated the tip
onto the nozzle or other hardware feature on the fluid handling
system.
Processing Units
In accordance with an embodiment of the invention, a preparation
station and/or assay station, or any other portion of a module or
device, may include one or more processing units. A processing unit
may be configured to prepare a sample for the performance and/or to
perform a biological or chemical reaction that yields a detectable
signal indicative of the presence or absence of one or more
analyte, and/or a concentration of a one or more analyte. The
processing unit may be used for preparing an assay sample or
performing any other process with respect to the sample or related
reagents, as provided in one or more sample preparation or
processing steps as described elsewhere herein. The processing unit
may have one or more characteristics of an assay unit as described
elsewhere herein. A processing unit may function as an assay unit
as described elsewhere herein.
A detectable signal may include an optical signal, visible signal,
electrical signal, magnetic signal, infrared signal, thermal
signal, motion, weight, or sound.
In some embodiments, a plurality of processing units may be
provided. In some embodiments, one or more row of processing units,
and/or one or more column of processing units may be provided. In
some embodiments, an m.times.n array of processing units may be
provided, wherein m, n are whole numbers. The processing units may
be provided in staggered rows or columns from each other. In some
embodiments, they may have any other configuration.
Any number of processing units may be provided. For example there
may be more than and/or equal to about 1, 2, 3, 4, 5, 8, 10, 15,
20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 175, 200, 250,
300, 400, 500, or 1000 processing units.
Processing units may be provided in a cartridge, card, or have any
other supporting structure. The processing units may have the same
orientation. Alternatively, processing units may have different
orientations. In some examples, processing units may be kept at a
vertical orientation. In other examples, processing units may have
horizontal or vertical orientations, or any other angle of
orientation. The processing units may remain the same or may vary
over time.
In some cases, a pipette, tip, or both may be integrated with a
cartridge or card. In some cases, tips or pipettes, or components
of tips or pipettes, are integrated with cartridges or cards.
The processing units may be fluidically isolated or hydraulically
independent from one another. The processing units may contain
and/or confine samples or other fluids that may be in fluid
isolation from one another. The samples and/or other fluids
contained within the processing units may be the same, or may vary
from unit to unit. The system may be capable of tracking what each
processing unit contains. The system may be capable of tracking the
location and history of each processing unit.
The processing units may be independently movable relative to one
another, or another portion of the device or module. Thus, the
fluids and/or samples contained therein may be independently
movable relative to one another or other portions of the device or
module. A processing unit may be individually addressable.
The location of each processing unit may be tracked. A processing
unit may be individually selected to receive and/or provide a
fluid. A processing unit may be individually selected to transport
a fluid. Fluid may be individually provided to or removed from a
processing unit. Fluid may be individually dispensed and/or
aspirated using the processing unit. A processing unit may be
independently detectable.
Any description herein of individual processing units may also
apply to groups of processing units. A group of processing units
may include one, two, or more processing units. In some
embodiments, processing units within a group may be moved
simultaneously. The location of groups of processing units may be
tracked. Fluids may be simultaneously delivered and/or aspirated
from one or more group of processing units. Detection may occur
simultaneously to processing units within one or more groups of
processing units.
The processing units may have the form or characteristics of any of
the tips or vessels as described elsewhere herein. For example, a
processing unit can be any of the tips or vessels described herein.
Any description herein of processing units may also apply to tips
or vessels, or any description of tips or vessels may also apply to
the processing units.
In some embodiments, a processing unit may be a processing tip. A
processing tip may have a first end and a second end. The first end
and second end may be opposing one another. The first end and/or
the second end may be open or closed. In some embodiments, both the
first and second ends may be open. In alternate embodiments, the
processing unit may have three, four, or more ends.
The processing tip may have an interior surface and an exterior
surface. A passageway may connect the first and second ends of the
processing tip. The passageway may be a conduit or channel. The
first and second ends of the processing tip may be in fluid
communication with one another. The diameter of the first end of
the processing tip may be greater than the diameter of the second
end of the processing tip. In some embodiments, the outer diameter
of the first end of the processing tip may be greater than the
outer diameter of the second end of the processing tip. An inner
diameter of the first end of the processing tip may be greater than
the inner diameter of the second end of the processing tip.
Alternatively, a diameter of the processing tip may be the same at
the first and second ends. In some embodiments, the second end may
be held below the first end of the processing tip. Alternatively
the relative positions of the first and second ends may vary.
In some embodiments, a processing unit may be a vessel. A
processing unit may have a first end and a second end. The first
end and second end may be opposing one another. The first end
and/or the second end may be open or closed. In some embodiments,
the second end may be held below the first end of the processing
unit. Alternatively the relative positions of the first and second
ends may vary. An open end of the processing unit may be oriented
upwards, or may be held higher than a closed end.
In some embodiments, a processing unit may have a cap or closure.
The cap or closure may be capable of blocking an open end of the
processing unit. The cap or closure may be selectively applied to
close or open the open end of the processing unit. The cap or
closure may have one or more configuration as illustrated elsewhere
herein or as known in the art. The cap or closure may form an
airtight seal that may separate the contents of the reagent unit
from the ambient environment. The cap or closure may include a
film, oil (e.g., mineral oil), wax, or gel.
As previously described regarding tips and/or vessels, a processing
unit may be picked up using a fluid handling device. For example, a
pipette or other fluid handling device may connect to the
processing unit. A pipette nozzle or orifice may interface with an
end of the processing unit. In some embodiments, a fluid-tight seal
may be formed between the fluid handling device and the processing
unit. A processing unit may be attached to and/or detached from the
fluid handling device. Any other automated device or process may be
used to move or manipulate a processing unit. A processing unit may
be moved or manipulated without the intervention of a human.
A fluid handling device or any other automated device may be able
to pick up or drop off an individual processing unit. A fluid
handling device or other automated device may be able to
simultaneously pick up or drop off a plurality of processing units.
A fluid handling device or other automated device may be able to
selectively pick up or drop off a plurality of processing units. In
some embodiments, a fluid handling device may be able to
selectively aspirate and/or dispense a sample using one, two or
more processing units.
Any description of fluid handling systems as described previously
herein may apply to the processing units.
In one embodiment, a processing unit may be formed from molded
plastic. The processing unit may be either commercially available
or can be made by injection molding with precise shapes and sizes.
The units can be coated with capture reagents or other materials
using method similar to those used to coat microtiter plates but
with the advantage that they can be processed in bulk by placing
them in a large vessel, adding coating reagents and processing
using sieves, holders, and the like to recover the pieces and wash
them as needed. In some embodiments, the capture reagents may be
provided on an interior surface of the processing units.
A processing unit can offer a rigid support on which a reactant can
be immobilized. The processing unit may also be chosen to provide
appropriate characteristics with respect to interactions with
light. For example, the processing unit can be made of a material,
such as functionalized glass, Si, Ge, GaAs, GaP, SiO.sub.2,
SiN.sub.4, modified silicon, or any one of a wide variety of gels
or polymers such as (poly)tetrafluoroethylene,
(poly)vinylidenedifluoride, polystyrene, polycarbonate,
polypropylene, Polymethylmethacylate (PMMA), ABS, or combinations
thereof. In an embodiment, a processing unit may comprise
polystyrene. Other appropriate materials may be used in accordance
with the present invention. Any of the materials described here,
such as those applying to tips and/or vessels may be used to form a
processing unit. A transparent reaction site may be advantageous.
In addition, in the case where there is an optically transmissive
window permitting light to reach an optical detector, the surface
may be advantageously opaque and/or preferentially light
scattering. The processing unit may optionally be opaque and not
permit the transmission of light therein.
A reactant may be immobilized at the capture surface of a
processing unit. In some embodiments, the capture surface is
provided on an interior surface of the processing unit. In one
example, the capture surface may be provided in a lower portion of
a processing tip or vessel.
The processing units can be dried following the last step of
incorporating a capture surface. For example, drying can be
performed by passive exposure to a dry atmosphere or via the use of
a vacuum manifold and/or application of clean dry air through a
manifold.
In some embodiments, rather than using a capture surface on the
processing unit, beads or other substrates may be provided to the
processing units with capture surfaces provided thereon. One or
more free-flowing substrate may be provided with a capture surface.
In some embodiments, the free-flowing substrate with a capture
surface may be provided within a fluid. In some embodiments, a bead
may be magnetic. The bead may be coated with one or more reagents
as known in the art. A magnetic bead may be held at a desired
location within the processing unit. The magnetic bead may be
positioned using one or more magnet.
Beads may be useful for conducting one or more assay, including but
not limited to immunoassay, nucleic acid assay, or any of the other
assays described elsewhere herein. The beads may be used during a
reaction (e.g., chemical, physical, biological reaction). The beads
may be used during one or more sample preparation step. The beads
may be coated with one or more reagent. The beads themselves may be
formed of reagents. The beads may be used for purification, mixing,
filtering, or any other processes. The beads may be formed of a
transparent material, translucent material, and/or opaque material.
The beads may be formed of a thermally conductive or thermally
insulative material. The beads may be formed of an electrically
conductive or electrically insulative material. The beads may
accelerate a sample preparation and/or assay step. The beads may
provide an increased surface area that may react with one or more
sample or fluid.
In alternate embodiments, beads or other solid materials may be
provided to the assay units. The beads may be configured to
dissolve under certain conditions. For example, the beads may
dissolve when in contact with a fluid, or when in contact with an
analyte or other reagents. The beads may dissolve at particular
temperatures.
The beads may have any size or shape. The beads may be spherical.
The beads may have a diameter of less than or equal to about 1 nm,
5 nm, 10 nm, 50 nm, 100 nm, 200 nm, 300 nm, 500 nm, 750 nm, 1
.mu.m, 2 .mu.m, 3 .mu.m, 5 .mu.m, 10 .mu.m, 20 .mu.m, 50 .mu.m, 100
.mu.m, 200 .mu.m, 300 .mu.m, 400 .mu.m, 500 .mu.m, 600 .mu.m, 700
.mu.m, 800 .mu.m, 900 .mu.m, 1 mm, 1.2 mm, 1.5 mm, 2 mm, 2.5 mm, 3
mm, 4 mm, or 5 mm. The beads may be of the same size or differing
sizes. The beads may include microparticles or nanoparticles.
A processing unit may have any dimension, including those described
elsewhere herein for tips and/or vessels. The processing unit may
be capable of containing and/or confining a small volume of sample
and/or other fluid, including volumes mentioned elsewhere
herein.
A processing unit may be picked up and/or removed from a fluid
handling mechanism. For example, a processing tip or other
processing unit may be picked up by a pipette nozzle. The
processing tip or other processing unit may be dropped off by a
pipette nozzle. In some embodiments, processing units may be
selectively individually picked up and/or dropped off. One or more
group of processing units may be selectively picked up and/or
dropped off. A processing unit may be picked up and/or dropped off
using an automated mechanism. A processing unit may be picked up
and/or dropped off without requiring human intervention. A pipette
may pick up and/or drop off a processing unit in accordance with
descriptions provided elsewhere herein.
A processing unit may be moved within a device and/or module using
a fluid handling mechanism.
For example, a processing tip/vessel or other processing unit may
be transported using a pipette head. The processing tip/vessel or
other processing unit may be transported in a horizontal direction
and/or vertical direction. The processing tip/vessel and/or
processing unit may be transported in any direction. The processing
unit may be moved individually using the fluid handling mechanism.
One or more groups of processing units may be simultaneously moved
using the fluid handling mechanism.
A processing unit may be shaped and/or sized to permit detection by
a detection unit. The detection unit may be provided external to,
inside, or integrated with the processing unit. In one example, the
processing unit may be transparent. The processing unit may permit
the detection of an optical signal, audio signal, visible signal,
electrical signal, magnetic signal, chemical signal, biological
signal, motion, acceleration, weight, or any other signal by a
detection unit.
A detector may be capable of detecting signals from individual
processing units. The detector may differentiate signals received
from each of the individual processing units. The detector may
individually track and/or follow signals from each of the
individual processing units. A detector may be capable of
simultaneously detecting signals from one or more groups of
processing units. The detector may track and/or follow signals from
the one or more groups of processing units.
In some embodiments, magnetic particles or superparamagnetic
nanoparticles may be used in conjunction with vessels and
miniaturized magnetic resonance to effect particular unit
operations. Magnetic particles or superparamagnetic nanoparticles
may be manipulated either via external magnetic fields, or via the
pipette/fluid transfer device. Magnetic beads may be used for
separations (when coated with antibodies/antigens/other capture
molecules), for mixing (via agitation by external magnetic field),
for concentrating analytes (either by selectively separating the
analyte, or by separating impurities), etc. All these unit
operations may be effectively carried out in small volumes with
high efficiencies.
Reagent Unit
In accordance with an embodiment of the invention, an assay
station, or any other portion of a module or device, may include
one or more reagent units. A reagent unit may be configured to
contain and/or confine a reagent that may be used in an assay. The
reagent within the reagent unit may be used in a biological or
chemical reaction. The reagent unit may store one or more reagent
prior to, during, or subsequent to a reaction that may occur with
the reagent. The biological and/or chemical reactions may or may
not take place external to the reagent units.
Reagents may include any of the reagents described in greater
detail elsewhere herein. For example, reagents may include a sample
diluent, a detector conjugate (for example, an enzyme-labeled
antibody), a wash solution, and an enzyme substrate. Additional
reagents can be provided as needed.
In some embodiments, a plurality of reagent units may be provided.
In some embodiments, one or more row of reagent units, and/or one
or more column of reagent units may be provided. In some
embodiments, an m.times.n array of reagent units may be provided,
wherein m, n are whole numbers. The reagent units may be provided
in staggered rows or columns from each other. In some embodiments,
they may have any other configuration.
Any number of reagent units may be provided. For example there may
be more than and/or equal to about 1, 2, 3, 4, 5, 8, 10, 15, 20,
25, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 175, 200, 250, 300,
400, 500, or 1000 reagent units.
Optionally, the same number of reagent units and assay units may be
provided. One or more reagent units may correspond to an assay
unit. One or more assay units may correspond to a reagent unit. One
or more reagent units may be movable relative to an assay unit.
Alternative, one or more assay unit may be movable relative to a
reagent unit. An assay unit may be individually movable relative to
a reagent unit.
Reagent units may be provided in a cartridge, card, or have any
other supporting structure. The reagent units may have the same
orientation. For example reagent units may have one or more open
end that may be facing in the same direction. Alternatively,
reagent units may have different orientations. In some examples,
reagent units may be kept at a vertical orientation. In other
examples, reagent units may have horizontal or vertical
orientations, or any other angle of orientation. The reagent units
may remain the same or may vary over time. Reagent units may be
provided on a supporting structure with assay units.
Alternatively, reagent units may be provided on separate supporting
structures than assay units. Reagent units and assay units may be
supported in separate portions of a supporting structure.
Alternatively, they may be intermingled on a supporting
structure.
The reagent units may be fluidically isolated or hydraulically
independent from one another. The reagent units may contain and/or
confine samples or other fluids that may be in fluid isolation from
one another. The samples and/or other fluids contained within the
reagent units may be the same, or may vary from unit to unit. The
system may be capable of tracking what each reagent unit contains.
The system may be capable of tracking the location and history of
each reagent unit.
The reagent units may be independently movable relative to one
another, or another portion of the device or module. Thus, the
fluids and/or samples contained therein may be independently
movable relative to one another or other portions of the device or
module. A reagent unit may be individually addressable.
The location of each reagent unit may be tracked. A reagent unit
may be individually selected to receive and/or provide a fluid. A
reagent unit may be individually selected to transport a fluid.
Fluid may be individually provided to or removed from a reagent
unit. A reagent unit may be independently detectable.
Any description herein of individual reagent units may also apply
to groups of reagent units. A group of reagent units may include
one, two, or more reagent units. In some embodiments, reagent units
within a group may be moved simultaneously. The location of groups
of reagent units may be tracked. Fluids may be simultaneously
delivered and/or aspirated from one or more group of reagent units.
Detection may occur simultaneously to assay units within one or
more groups of assay units.
The reagent units may have the form or characteristics of any of
the tips or vessels as described elsewhere herein. For example, a
reagent unit can be any of the tips or vessels described herein.
Any description herein of reagent units may also apply to tips or
vessels, or any description of tips or vessels may also apply to
the reagent units.
In some embodiments, a reagent unit may be a vessel. A reagent unit
may have a first end and a second end. The first end and second end
may be opposing one another. The first end and/or the second end
may be open or closed. In some embodiments, a first end may be open
and a second end may be closed. In alternate embodiments, the assay
unit may have three, four, or more ends. The vessel may be covered
by a septum and/or barrier to prevent evaporation and/or
aerosolization to prevent reagent loss and contamination of the
device. The vessel may be disposable. This eliminates the
requirement of externally filling reagents from a common source.
This also allows better quality control and handling of reagents.
Additionally, this reduces contamination of the device and the
surroundings.
The reagent unit may have an interior surface and an exterior
surface. A passageway may connect the first and second ends of the
reagent unit. The passageway may be a conduit or channel. The first
and second ends of the assay tip may be in fluid communication with
one another. The diameter of the first end of the reagent unit may
be greater than the diameter of the second end of the reagent unit.
In some embodiments, the outer diameter of the first end of the
reagent unit may be greater than the outer diameter of the second
end of the reagent unit. Alternatively, the diameters may be the
same, or the outer diameter of the second end may be greater than
the outer diameter of the first end. An inner diameter of the first
end of the reagent unit may be greater than the inner diameter of
the second end of the reagent unit. Alternatively, a diameter
and/or inner diameter of the reagent unit may be the same at the
first and second ends. In some embodiments, the second end may be
held below the first end of the reagent unit. Alternatively the
relative positions of the first and second ends may vary. An open
end of the reagent unit may be oriented upwards, or may be held
higher than a closed end.
In some embodiments, a reagent unit may have a cap or closure. The
cap or closure may be capable of blocking an open end of the
reagent unit. The cap or closure may be selectively applied to
close or open the open end of the reagent unit. The cap or closure
may have one or more configuration as illustrated elsewhere herein
or as known in the art. The cap or closure may form an airtight
seal that may separate the contents of the reagent unit from the
ambient environment.
As previously described regarding tips and/or vessels, a reagent
unit may be picked up using a fluid handling device. For example, a
pipette or other fluid handling device may connect to the reagent
unit. A pipette nozzle or orifice may interface with an end of the
reagent unit. In some embodiments, a fluid-tight seal may be formed
between the fluid handling device and the reagent unit. A reagent
unit may be attached to and/or detached from the fluid handling
device. The fluid handling device may move the reagent unit from
one location to another. Alternatively, the reagent unit is not
connected to the fluid handling device. Any other automated device
or process may be used to move or manipulate an assay unit. A
reagent unit may be moved or manipulated without the intervention
of a human.
A reagent unit may be configured to accept an assay unit. In some
embodiments, a reagent unit may include an open end through which
at least a portion of an assay unit may be inserted. In some
embodiments, the assay unit may be entirely inserted within the
reagent unit. An open end of the reagent unit may have a greater
diameter than at least one of the open ends of the assay unit. In
some instances, an inner diameter of an open end of the reagent
unit may be greater than an outer diameter of at least one of the
open ends of the assay unit. In some embodiments, a reagent unit
may be shaped or may include one or more feature that may permit
the assay unit to be inserted a desired amount within the reagent
unit. The assay unit may or may not be capable of being inserted
completely into the reagent unit.
An assay unit may dispense to and/or aspirate a fluid from the
reagent unit. A reagent unit may provide a fluid, such as a
reagent, that may be picked up by the assay unit. The assay unit
may optionally provide a fluid to the reagent unit. Fluid may be
transferred through the open end of a reagent unit and an open end
of the assay unit. The open ends of the assay unit and the reagent
unit may permit the interior portions of the assay unit and the
reagent unit to be brought into fluid communication with one
another. In some embodiments, an assay unit may be located above
the reagent unit during said dispensing and/or aspiration.
Alternatively, fluid transfer between the reagent unit and the
assay unit may be done by a fluid handling device. One or several
such fluid transfers might happen simultaneously. The fluid
handling device in one embodiment might be a pipette.
In one example, a reagent for a chemical reaction may be provided
within a reagent unit. An assay unit may be brought into the
reagent unit and may aspirate the reagent from the reagent unit. A
chemical reaction may occur within the assay unit. The excess fluid
from the reaction may be dispensed from the assay unit. The assay
unit may pick up a wash solution. The wash solution may be expelled
from the assay unit.
The washing step may occur one, two, three, four, five, or more
times. The wash solution may optionally be picked up and/or
dispensed to a reagent unit. This may reduce background signal
interference. A detector may detect one or more signal from the
assay unit. The reduced background signal interference may permit
increased sensitivity of signals detected from the assay unit. An
assay tip format may be employed, which may advantageously provide
easy expulsion of fluids for improved washing conditions.
A fluid handling device or any other automated device may be able
to pick up or drop off an individual assay unit. A fluid handling
device or other automated device may be able to simultaneously pick
up or drop off a plurality of assay units. A fluid handling device
or other automated device may be able to selectively pick up or
drop off a plurality of assay units. In some embodiments, a fluid
handling device may be able to selectively aspirate and/or dispense
a sample using one, two or more assay units. Any description of
fluid handling systems as described previously herein may apply to
the assay units.
In one embodiment, a reagent unit may be formed from molded
plastic. The reagent unit may be either commercially available or
can be made by injection molding with precise shapes and sizes. The
units can be coated with capture reagents using method similar to
those used to coat microtiter plates but with the advantage that
they can be processed in bulk by placing them in a large vessel,
adding coating reagents and processing using sieves, holders, and
the like to recover the pieces and wash them as needed. In some
embodiments, the capture reagents may be provided on an interior
surface of the reagent units. Alternatively reagent units may be
uncoated, or may be coated with other substances.
A reagent unit can offer a rigid support. The reagent unit may be
chosen to provide appropriate characteristics with respect to
interactions with light. For example, the reagent unit can be made
of a material, such as functionalized glass, Si, Ge, GaAs, GaP,
SiO.sub.2, SiN.sub.4, modified silicon, or any one of a wide
variety of gels or polymers such as (poly)tetrafluoroethylene,
(poly)vinylidenedifluoride, polystyrene, polycarbonate,
polypropylene, PMMA, ABS, or combinations thereof. In an
embodiment, an assay unit may comprise polystyrene. Other
appropriate materials may be used in accordance with the present
invention. Any of the materials described here, such as those
applying to tips and/or vessels may be used to form a reagent unit.
A transparent reaction site may be advantageous. In addition, in
the case where there is an optically transmissive window permitting
light to reach an optical detector, the surface may be
advantageously opaque and/or preferentially light scattering.
A reagent unit may or may not offer a capture surface, such as
those described for assay units.
Similarly, a reagent unit may or may not employ beads or other
substrates to provide capture surfaces. Any description relating to
beads or other capture surfaces for assay units or processing units
may also optionally be applied to reagent units.
A reagent unit may or may not have a reaction site. Any description
herein of a reaction site for an assay unit may also apply to a
reagent unit.
A reagent unit may have any dimension, including those described
elsewhere herein for tips and/or vessels. The reagent unit may be
capable of containing and/or confining a small volume of sample
and/or other fluid, including volumes mentioned elsewhere
herein.
A reagent unit may be stationary within a device and/or module.
Alternatively, a reagent unit may be movable relative to the device
and/or module. A reagent unit may be picked up and/or moved using a
fluid handling mechanism or any other automated process. For
example, a reagent unit may be picked up by a pipette nozzle, such
as in a manner described elsewhere for an assay unit.
Relative movement may occur between the assay unit and the reagent
unit. The assay unit and/or reagent unit may move relative to one
another. Assay units may move relative to one another. Reagent
units may move relative to one another. Assay units and/or reagent
units may be individually movable relative to the device and/or
module.
A reagent unit may be shaped and/or sized to permit detection by a
detection unit. The detection unit may be provided external to,
inside, or integrated with the reagent unit. In one example, the
reagent unit may be transparent. The reagent unit may permit the
detection of an optical signal, audio signal, visible signal,
electrical signal, magnetic signal, motion, acceleration, weight,
or any other signal by a detection unit.
A detector may be capable of detecting signals from individual
reagent units. The detector may differentiate signals received from
each of the individual reagent units. The detector may individually
track and/or follow signals from each of the individual reagent
units. A detector may be capable of simultaneously detecting
signals from one or more groups of reagent units. The detector may
track and/or follow signals from the one or more groups of reagent
units. Alternatively, the detector need not detect signals from
individual reagents. In some embodiments the device and/or system
may keep track of the identity of reagents or other fluids provided
within the reagent units, or information associated with the
reagents or other fluids.
As previously mentioned reagent units may include one or more
reagents therein. Reagents may include a wash buffer, enzyme
substrate, dilution buffer, or conjugates (such as enzyme labeled
conjugates).
Examples of enzyme labeled conjugates may include polyclonal
antibodies, monoclonal antibodies, or may be labeled with enzyme
that can yield a detectable signal upon reaction with an
appropriate substrate. Reagents may also include DNA amplifiers,
sample diluents, wash solutions, sample pre-treatment reagents
(including additives such as detergents), polymers, chelating
agents, albumin-binding reagents, enzyme inhibitors, enzymes (e.g.,
alkaline phosphatase, horseradish peroxide), anticoagulants,
red-cell agglutinating agents, or antibodies. Any other examples of
reagents described elsewhere herein may also be contained and/or
confined within a reagent unit.
Dilution
The device and/or module may permit the use of one or more diluents
in accordance with an embodiment of the invention. Diluent may be
contained in one or more reagent unit, or any other unit that may
contain and/or confine the diluents. The diluents may be provided
in a tip, vessel, chamber, container, channel, tube, reservoir, or
any other component of the device and/or module. Diluent may be
stored in a fluidically isolated or hydraulically independent
component. The fluidically isolated or hydraulically independent
component may be stationary or may be configured to move relative
to one or more portion of the device and/or module.
In some embodiments, diluents may be stored in diluents units,
which may have any characteristics of reagent units as described
elsewhere herein. The diluents units may be stored in the same
location as the rest of the reagent units, or may be stored
remotely relative to the rest of the reagent units.
Any examples of diluents known in the art may be employed. Diluent
may be capable of diluting or thinning a sample. In most instances,
the diluents do not cause a chemical reaction to occur with the
sample.
A device may employ one type of diluents. Alternatively, the device
may have available or employ multiple types of diluents. The system
may be capable of tracking diluents and/or various types of
diluents. Thus, the system may be capable of accessing a desired
type of diluents. For example, a tip may pick up a desired
diluent.
In some embodiments, diluents may be provided to a sample. The
diluents may dilute the sample.
The sample may become less concentrated with the addition of a
diluent. The degree of dilution may be controlled according to one
or more protocol or instructions. In some instances, the protocol
or instructions may be provided from an external device, such as a
server. Alternatively, the protocol or instructions may be provided
on-board the device or cartridge or vessel. Thus, a server and/or
the device may be capable of variable dilution control. By
controlling the degree of dilution, the system may be capable of
detecting the presence or concentration of one or more analytes
that may vary over a wide range. For example, a sample may have a
first analyte having a concentration that would be detectable over
a first range, and a second analyte having a concentration that
would be detectable over the second range. The sample may be
divided and may or may not have varying amounts of diluents applied
to bring the portions of the sample into a detectable range for the
first and second analytes. Similarly, a sample may or may not
undergo varying degrees of enrichment to bring analytes to a
desired concentration for detection.
Dilution and/or enrichment may permit the one, two, three or more
analytes having a wide range of concentrations to be detected. For
examples, analytes differing by one or more, two or more, three or
more, four or more, five or more, six or more, seven or more, eight
or more, nine or more, or ten or more degrees of magnitude may be
detected from a sample.
In some embodiments, a sample may be combined with diluents in an
assay tip or other type of tip described elsewhere herein. An assay
tip may aspirate a diluent. The assay tip may pick up the diluents
from a reagent unit. The diluents may or may not be combined with
the sample within the assay tip.
In another example, a diluents and/or sample may be combined in a
reagent unit or other types of vessels described elsewhere herein.
For example, a diluents may be added to a sample in a reagent unit,
or a sample may be added to a diluents in the reagent unit.
In some embodiments, one or more mixing mechanism may be provided.
Alternatively, no separate mixing mechanism is needed. The assay
unit, reagent unit, or any other tip, vessel, or compartment
combining a sample and diluents may be capable of moving, thereby
effecting a mixing.
Varying amounts of diluents and/or samples may be combined to
achieve a desired level of dilution.
Protocols may determine the relative proportion of diluents and
sample to combine. In some embodiments, the portion of sample to
diluent may be less than and/or equal to about 1:1,000,000,
1:100,000, 1:10,000, 1:1,000, 1:500, 1:100, 1:50, 1:10, 1:5, 1:3,
1:2, 1:1, or greater than and/or equal to 2:1, 3:1, 5:1, 10:1,
50:1, 100:1, 500:1, 1,000:1, 10,000:1, 100,000:1, or 1,000,000:1.
The diluted sample may be picked up from the reagent unit using an
assay tip, where one or more chemical reaction may occur.
A desired amount of diluents may be provided in accordance with one
or more set of instructions. In some embodiments, the amount of
dilution provided may be controlled by a fluid handling system. For
example, an assay tip may pick up a desired amount of diluents and
dispense it to a desired location. The volume of diluents picked up
by the assay tip may be controlled with a high degree of
sensitivity. For example, the amount of diluents picked up may have
any of the volumes of fluids or samples discussed elsewhere herein.
In some embodiments, an assay tip may pick up a desired amount of
diluents in one turn. Alternatively, an assay tip may pick up and
dispense diluents multiple times in order to achieve a desired
degree of dilution.
Dilution of a sample may occur during a sample pre-treatment step.
A sample may be diluted prior to undergoing a chemical reaction.
Alternatively, dilution may occur during a chemical reaction and/or
subsequent to a chemical reaction.
The dilution factor may be optimized in real-time for each assay
depending on the assay requirements. In one embodiment, real-time
determination of a dilution scheme can be performed by knowledge of
all assays to be performed. This optimization may take advantage of
multiple assays using identical dilution. The aforementioned
dilution scheme may result in higher precision of final diluted
sample.
Dilution of a sample may be performed serially or in a single step.
For a single-step dilution, a selected quantity of sample may be
mixed with a selected quantity of diluent, in order to achieve a
desired dilution of the sample. For a serial dilution, two or more
separate sequential dilutions of the sample may be performed in
order to achieve a desired dilution of the sample. For example, a
first dilution of the sample may be performed, and a portion of
that first dilution may be used as the input material for a second
dilution, to yield a sample at a selected dilution level.
For dilutions described herein, an "original sample" refers to the
sample that is used at the start of a given dilution process. Thus,
while an "original sample" may be a sample that is directly
obtained from a subject, it may also include any other sample (e.g.
sample that has been processed or previously diluted in a separate
dilution procedure) that is used as the starting material for a
given dilution procedure.
In some embodiments, a serial dilution of a sample may be performed
with a device described herein as follows. A selected quantity
(e.g. volume) of an original sample may be mixed with a selected
quantity of diluent, to yield a first dilution sample. The first
dilution sample (and any subsequent dilution samples) will have: i)
a sample dilution factor (e.g. the amount by which the original
sample is diluted in the first dilution sample) and ii) an initial
quantity (e.g. the total quantity of the first dilution sample
present after combining the selected quantity of original sample
and selected quantity of diluent). For example, 10 microliters of
an original sample may be mixed with 40 microliters of diluent, to
yield a first dilution sample having a 5-fold dilution factor and
an initial quantity of 50 microliters. Next, a selected quantity of
the first dilution sample may be mixed with a selected quantity of
diluent, to yield a second dilution sample. For example, 5
microliters of the first dilution sample may be mixed with 95
microliters of diluent, to yield a second dilution sample having an
100-fold dilution factor and an initial quantity of 100
microliters. For each of the above dilution steps, the original
sample, dilution sample(s), and diluent may be stored or mixed in
fluidically isolated vessels. Sequential dilutions may continue in
the preceding manner for as many steps as needed to reach a
selected sample dilution level/dilution factor.
In devices provided herein, an original sample may be diluted, for
example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35,
40, 50, 75, 100, 200, 300, 400, 500, 1,000, 5,000, 10,000, 20,000,
50,000, or 100,000-fold, by either a single-step or serial dilution
procedure. In some embodiments, a single original sample may be
diluted to reach multiple different selected sample dilution
factors (e.g. a single original sample may be diluted to generate
samples which are diluted 5-fold, 10-fold, 25-fold, 100-fold,
200-fold, 500-fold, and 1000-fold). In some embodiments, a device
may be configured to perform a 2, 3, 4, 5, 6, 7, 8, 9, 10, or more
step serial dilution. A device may be configured to dilute 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, or more different original samples within the
same device (e.g. a device may dilute both EDTA-containing and
heparin-containing plasma samples at the same time). In some
embodiments, a device provided herein contains a controller which
is configured to instruct a sample handling system within the
device to perform one or more sample handling steps to prepare any
of the dilutions of sample described above or elsewhere herein. The
controller may direct the device to use 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, or more different diluents for different dilution procedures.
The controller may contain a protocol for performing the dilutions.
The protocol may be stored or generated on-the-fly. The protocol
may be sent from an external device to the sample processing
device, or stored or generated on the sample processing device.
In some embodiments, one or more steps of a dilution procedure may
be performed with a sample handling system. The sample handling
system may be a pipette or other fluid handling apparatus. The
sample handling system may be configured for obtaining a selected
quantity of a sample or diluent from a fluidically isolated vessel
containing the sample or diluent, and transporting the selected
quantity of sample or diluent to a different fluidically isolated
vessel. During the dilution of a sample, the diluent may be
deposited in a vessel before the sample is added to the diluent.
Alternatively, the sample may be deposited in a vessel before the
diluent is added to the sample. In other embodiments, the sample
and diluent may be in the same fluid circuit.
Dilution of samples may facilitate the performance of a large
number of assays with a small amount of original sample. In some
situations, dilution of an original sample into multiple dilution
samples having different dilution factors may, for example: i)
reduce waste of sample, for example, by only using the minimum
amount of original sample required to perform each assay (i.e. by
not using samples that are more concentrated than necessary to
perform the assay); ii) increase the total number of assays that
may be performed with a given amount of original sample, for
example, by the reduction of waste of sample; and iii) increase the
variety of assays that may be performed with an original sample,
for example, by dilution of the original sample to different sample
dilution factors, where different sample dilution factors are
needed to perform different assays (for example, if one assay
requires a high sample concentration in order to efficiently detect
an analyte that is not abundant in the sample, and if another assay
requires a low sample concentration in order to efficiently detect
an analyte that is abundant in the sample).
Washing
The device and/or module may permit washing in accordance with an
embodiment of the invention.
A wash solution may be contained in one or more reagent unit, or
any other unit that may contain and/or confine the wash solution.
The wash solution may be provided in a tip, vessel, chamber,
container, channel, tube, reservoir, or any other component of the
device and/or module. A wash solution may be stored in a
fluidically isolated or hydraulically independent component. The
fluidically isolated or hydraulically independent component may be
stationary or may be configured to move relative to one or more
portion of the device and/or module.
In some embodiments, wash solution may be stored in wash units,
which may have any characteristics of reagent units as described
elsewhere herein. The wash units may be stored in the same location
as the rest of the reagent units, or may be stored remotely
relative to the rest of the reagent units.
Any examples of wash solutions known in the art may be employed.
Wash solutions may be capable of removing unbound and/or unreacted
reactants. For examples, a chemical reaction may occur between a
sample containing an analyte and an immobilized reactant, that may
cause an analyte to bind to a surface.
The unbound analytes may be washed away. In some embodiments, a
reaction may cause the emission of an optical signal, light, or any
other sort of signal. If unreacted reactants remain in the
proximity, they may cause interfering background signal. It may be
desirable to remove the unreacted reactants to reduce interfering
background signal and permit the reading of the bound analytes. In
some instances, the wash solution does not cause a chemical
reaction to occur between the wash solution and the sample.
A device may employ one type of wash solutions. Alternatively, the
device may have available or employ multiple types of wash
solutions. The system may be capable of tracking wash solutions
and/or various types of wash solutions. Thus, the system may be
capable of accessing a desired type of wash solution. For example,
a tip may pick up a desired wash solution.
In some embodiments, a wash solution may be provided to a sample.
The wash solution may dilute the sample. The sample may become less
concentrated with the addition of a wash solution. The degree of
washing may be controlled according to one or more protocol or
instructions. By controlling the degree of washing, the system may
be capable of detecting the presence or concentration of one or
more analytes with a desired sensitivity. For example, increased
amounts of washing may remove undesirable reagents or sample that
may cause interfering background noise.
In some embodiments, a wash solution may be provided to an assay
tip or other type of tip described elsewhere herein. An assay tip
may aspirate a wash solution. The assay tip may pick up the wash
solutions from a wash unit. The wash solution may or may not be
dispensed back out through the assay tip. The same opening of an
assay tip may both aspirate and dispense the wash solution. For
example, an assay tip may have a bottom opening that may be used to
both pick up and expel a wash solution. The assay tip may have both
a bottom opening and a top opening, where the bottom opening may
have a smaller diameter than the top opening. Expelling the wash
solution through the bottom opening may permit more effective
expulsion of the wash solution than if the bottom of the assay tip
were closed.
In another example, a wash solution and/or sample may be combined
in a reagent unit or other types of vessels described elsewhere
herein. For example, a wash solution may be added to a sample in a
reagent unit, or a sample may be added to a wash solution in the
reagent unit. The wash solution may be expelled in any manner. In
some embodiments, a combination of the wash solution and/or sample
may be picked up by an assay tip.
A desired amount of wash solution may be provided in accordance
with one or more set of instructions. In some embodiments, the
amount of wash solution provided may be controlled by a fluid
handling system. For example, an assay tip may pick up a desired
amount of wash solution and dispense it.
The volume of wash solution picked up by the assay tip may be
controlled with a high degree of sensitivity.
For example, the amount of wash solution picked up may have any of
the volumes of fluids or samples discussed elsewhere herein. In
some embodiments, an assay tip may pick up a desired amount of wash
solution in one turn. Alternatively, an assay tip may pick up and
dispense wash solution multiple times in order to achieve a desired
degree of washing.
Varying numbers of wash cycles may occur to provide a desired
sensitivity of detection. Protocols may determine the number of
wash cycles. For example, greater than, and/or equal to about one,
two, three, four, five, six, seven, eight, nine, ten, eleven, or
twelve wash cycles may occur. The wash solution may be picked up
from the wash unit using an assay tip, and may be expelled from the
assay tip.
Washing may occur subsequent to undergoing a chemical reaction.
Alternatively, washing may occur during a chemical reaction and/or
prior to a chemical reaction.
Contamination Reduction
The device and/or module may permit contamination prevention and/or
reduction in accordance with an embodiment of the invention. For
example, a touch-off pad may be provided. The touch-off pad may be
formed of an absorbent material. For example, the touch-off pad may
be a sponge, textile, gel, porous material, capillary or have any
feature that may absorb or wick away a fluid that may come into
contact with the pad. An assay tip may be brought into contact with
the touch-off pad, which may result in fluid from the assay tip in
proximity to the touch-off pad being absorbed by the pad. In some
embodiments, an assay tip may be brought to a touch-off pad in a
manner such that the assay tip does not contact a portion of the
pad that has previously been contacted. In some instances, liquid
is not placed in the same place as a liquid has been previously
touched off. The assay tips may be brought to the pad in a way so
that the contact points are spaced apart so that a different
contact point is used whenever an assay tip touches the pad. One or
more controller may determine the location of the touch-off pad
that an assay tip may contact next. The controller may keep track
of what points on the pad have already been contacted by an assay
tip. The assay pad may be absorbent.
The assay tip may be wiped by the pad. The excess fluid or
undesired fluid from the assay tip may be removed from the assay
tip. For example, an open end, such as a bottom end, of the assay
tip may be brought into contact with the touch-off pad. The pad may
be formed from an absorbent material that may wick the fluid away
from the assay tip. Thus, as an assay tip, or other component of
the device, may move throughout a module and/or device, the
likelihood of excess fluid or undesired fluid from contaminating
other portions of the module and/or device may be reduced. In one
non-limiting example, an absorbent pad is part of the cartridge and
it is configured to wick fluid away from tips, reducing carry over.
In some embodiments, an absorbant pad may be any location in a
device accessible by a sample handling system. Use of an absorbent
pad with pipetting or other tip-related liquid transfer methods may
increase the accuracy and precision of the fluid transfer and may
lower the coefficient of variation of transferring fluid with the
liquid transfer methods.
Another example of a contamination prevention and/or reduction
mechanism may include applying a coating or covering to an assay
tip or other component of the device. For example, an assay tip may
be brought into contact with a melted wax, oil (such as mineral
oil), or a gel. In some embodiments, the wax, oil, or gel may
harden. Hardening may occur as the material cools and/or is exposed
to air. Alternatively, they need not harden. The coating surface,
such as a wax, oil, or gel, may be sufficiently viscous to remain
on the assay tip or other component of the device. In one example,
an open end of the assay tip may be brought into contact with the
coating material, which may cover the open end of the assay tip,
sealing the contents of the assay tip.
Additional examples of contamination prevention and/or reduction
may be a waste chamber to accept used assay tips, a component that
may put one or more cap on used portions of assay tips, a heater or
fan, or ultraviolet light emitted onto one or more components or
subsystems, or any other component that may reduce the likelihood
of contamination any other component that may reduce the likelihood
of contamination.
In some embodiments, the fluid handling components of the device do
not require regular decontamination as the fixed components of the
device do not normally come in direct contact with the sample. The
fluid handling device may be capable of periodical
self-sanitization, such as by aspirating cleaning agents (e.g.,
ethanol) from a tank using the pipette. The fluid handling
apparatus, and other device resources, can also be decontaminated,
sterilized, or disinfected by a variety of other methods, including
UV irradiation.
Filter
The device and/or modules may include other components, which may
permit one or more function as described elsewhere herein. For
example, the device and/or module may have a filter that may permit
the separation of a sample by particle size, density, or any other
feature. For example, a particle or fluid having a particle size
smaller than a threshold size may pass through a filter while other
particles having a size greater than the threshold size do not. In
some embodiments, a plurality of filters may be provided. The
plurality of filters may have the same size or different sizes,
which may permit sorting of different sizes of particles into any
number of groups.
Centrifuge
In accordance with some embodiments of the invention, a system may
include one or more centrifuge. A device may include one or more
centrifuge therein. For example, one or more centrifuge may be
provided within a device housing. A module may have one or more
centrifuge. One, two, or more modules of a device may have a
centrifuge therein. The centrifuge may be supported by a module
support structure, or may be contained within a module housing. The
centrifuge may have a form factor that is compact, flat and
requires only a small footprint. In some embodiments, the
centrifuge may be miniaturized for point-of-service applications
but remain capable of rotating at high rates, equal to or exceeding
about 10,000 rpm, and be capable of withstanding g-forces of up to
about 1200 m/s.sup.2 or more.
A centrifuge may be configured to accept one or more sample. A
centrifuge may be used for separating and/or purifying materials of
differing densities. Examples of such materials may include
viruses, bacteria, cells, proteins, environmental compositions, or
other compositions. A centrifuge may be used to concentrate cells
and/or particles for subsequent measurement.
A centrifuge may have one or more cavity that may be configured to
accept a sample. The cavity may be configured to accept the sample
directly within the cavity, so that the sample may contact the
cavity wall. Alternatively, the cavity may be configured to accept
a sample vessel that may contain the sample therein. Any
description herein of cavity may be applied to any configuration
that may accept and/or contain a sample or sample container. For
example, cavities may include indentations within a material,
bucket formats, protrusions with hollow interiors, members
configured to interconnect with a sample container. Any description
of cavity may also include configurations that may or may not have
a concave or interior surface.
Examples of sample vessels may include any of the vessel or tip
designs described elsewhere herein. Sample vessels may have an
interior surface and an exterior surface. A sample vessel may have
at least one open end configured to accept the sample. The open end
may be closeable or sealable. The sample vessel may have a closed
end. The sample vessel may be a nozzle of the fluid handling
apparatus, which apparatus may act as a centrifuge to spin a fluid
in the nozzle, the tip or another vessel attached to such a
nozzle.
A centrifuge may have one or more, two or more, three or more, four
or more, five or more, six or more, eight or more, 10 or more, 12
or more, 15 or more, 20 or more, 30 or more, or 50 or more cavities
configured to accept a sample or sample vessel.
In some embodiments, the centrifuge may be configured to accept a
small volume of sample. In some embodiments, the cavity and/or
sample vessel may be configured to accept a sample volume of 1,000
.mu.L or less, 500 .mu.L or less, 250 .mu.L or less, 200 .mu.L or
less, 175 .mu.L or less, 150 .mu.L or less, 100 .mu.L or less, 80
.mu.L or less, 70 .mu.L or less, 60 .mu.L or less, 50 .mu.L or
less, 30 .mu.L or less, 20 .mu.L or less, 15 .mu.L or less, 10
.mu.L or less, 8 .mu.L or less, 5 .mu.L or less, 1 .mu.L or less,
500 nL or less, 300 nL or less, 100 nL or less, 50 nL or less, 10
nL or less, 1 nL or less, 500 pL or less, 100 pL or less 50 pL or
less, 10 pL or less 5 pL or less, or 1 pL or less. In some
embodiments, centrifuge may be configured such that the total
volume that the centrifuge is configured to accept (e.g. the
combined volume that may be accepted by the total of all the
cavities and/or sample vessels in the centrifuge) is 10 ml or less,
5 ml or less, 4 ml or less, 3 ml or less, 2 ml or less, 1 ml or
less, 750 .mu.l or less, 500 .mu.l or less, 400 .mu.l or less, 300
.mu.l or less, 200 .mu.l or less, 100 .mu.l or less, 50 .mu.l or
less, 40 .mu.l or less, 30 .mu.l or less, 20 .mu.l or less, 10
.mu.l or less, 8 .mu.l or less, 6 .mu.l or less, 4 .mu.l or less,
or 2 .mu.l or less. In some embodiments, the centrifuge may contain
50 or less, 40 or less, 30 or less, 29 or less, 28 or less, 27 or
less, 26 or less, 25 or less, 24 or less, 23 or less, 22 or less,
21 or less, 20 or less, 19 or less, 18 or less, 17 or less, 16 or
less, 15 or less, 14 or less, 13 or less, 12 or less, 11 or less,
10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less,
4 or less, 3 or less, 2 or less, or 1 cavities and/or sample
vessels, which are configured to accept, in total, a volume of 10
ml or less, 5 ml or less, 4 ml or less, 3 ml or less, 2 ml or less,
1 ml or less, 750 .mu.l or less, 500 .mu.l or less, 400 .mu.l or
less, 300 .mu.l or less, 200 .mu.l or less, 100 .mu.l or less, 50
.mu.l or less, 40 .mu.l or less, 30 .mu.l or less, 20 .mu.l or
less, 10 .mu.l or less, 8 .mu.l or less, 6 .mu.l or less, 4 .mu.l
or less, or 2 .mu.l or less.
In some embodiments, the centrifuge may have a cover that may
contain the sample within the centrifuge. The cover may prevent the
sample for aerosolizing and/or evaporating. The centrifuge may
optionally have a film, oil (e.g., mineral oil), wax, or gel that
may contain the sample within the centrifuge and/or prevent it from
aerosolizing and/or evaporating. The film, oil, wax, or gel may be
provided as a layer over a sample that may be contained within a
cavity and/or sample vessel of the centrifuge.
A centrifuge may be configured to rotate about an axis of rotation.
A centrifuge may be able to spin at any number of rotations per
minute. For example, a centrifuge may spin up to a rate of 100 rpm,
1,000 rpm, 2,000 rpm, 3,000 rpm, 5,000 rpm, 7,000 rpm, 10,000 rpm,
12,000 rpm, 15,000 rpm, 17,000 rpm, 20,000 rpm, 25,000 rpm, 30,000
rpm, 40,000 rpm, 50,000 rpm, 70,000 rpm, or 100,000 rpm. At some
points in time, a centrifuge may remain at rest, while at other
points in time, the centrifuge may rotate. A centrifuge at rest is
not rotating. A centrifuge may be configured to rotate at variable
rates. In some embodiments, the centrifuge may be controlled to
rotate at a desirable rate. In some embodiments, the rate of change
of rotation speed may be variable and/or controllable.
In some embodiments, the axis of rotation may be vertical.
Alternatively, the axis of rotation may be horizontal, or may have
any angle between vertical and horizontal (e.g., about 15, 30, 45,
60, or 75 degrees). In some embodiments, the axis of rotation may
be in a fixed direction. Alternatively, the axis of rotation may
vary during the use of a device. The axis of rotation angle may or
may not vary while the centrifuge is rotating.
A centrifuge may comprise a base. The base may have a top surface
and a bottom surface. The base may be configured to rotate about
the axis of rotation. The axis of rotation may be orthogonal to the
top and/or bottom surface of the base. In some embodiments, the top
and/or bottom surface of the base may be flat or curved. The top
and bottom surface may or may not be substantially parallel to one
another.
In some embodiments, the base may have a circular shape. The base
may have any other shape including, but not limited to, an
elliptical shape, triangular shape, quadrilateral shape, pentagonal
shape, hexagonal shape, or octagonal shape.
The base may have a height and one or more lateral dimension (e.g.,
diameter, width, or length). The height of the base may be parallel
to the axis of rotation. The lateral dimension may be perpendicular
to the axis of rotation. The lateral dimension of the base may be
greater than the height. The lateral dimension of the base may be 2
times or more, 3 times or more, 4 times or more, 5 times or more, 6
times or more, 8 times or more, 10 times or more, 15 times or more,
or 20 times or more greater than the height.
The centrifuge may have any size. For example, the centrifuge may
have a footprint of about 200 cm.sup.2 or less, 150 cm.sup.2 or
less, 100 cm.sup.2 or less, 90 cm.sup.2 or less, 80 cm.sup.2 or
less, 70 cm.sup.2 or less, 60 cm.sup.2 or less, 50 cm.sup.2 or
less, 40 cm.sup.2 or less, 30 cm.sup.2 or less, 20 cm.sup.2 or
less, 10 cm.sup.2 or less, 5 cm.sup.2 or less, or 1 cm.sup.2 or
less. The centrifuge may have a height of about 5 cm or less, 4 cm
or less, 3 cm or less, 2.5 cm or less, 2 cm or less, 1.75 cm or
less, 1.5 cm or less, 1 cm or less, 0.75 cm or less, 0.5 cm or
less, or 0.1 cm or less. In some embodiments, the greatest
dimension of the centrifuge may be about 15 cm or less, 10 cm or
less, 9 cm or less, 8 cm or less, 7 cm or less, 6 cm or less, 5 cm
or less, 4 cm or less, 3 cm or less, 2 cm or less, or 1 cm or
less.
The centrifuge base may be configured to accept a drive mechanism.
A drive mechanism may be a motor, or any other mechanism that may
enable the centrifuge to rotate about an axis of rotation. The
drive mechanism may be a brushless motor, which may include a
brushless motor rotor and a brushless motor stator. The brushless
motor may be an induction motor. The brushless motor rotor may
surround the brushless motor stator. The rotor may be configured to
rotate about a stator about an axis of rotation.
The base may be connected to or may incorporate the brushless motor
rotor, which may cause the base to rotate about the stator. The
base may be affixed to the rotor or may be integrally formed with
the rotor. The base may rotate about the stator and a plane
orthogonal to the axis of rotation of the motor may be coplanar
with a plane orthogonal to the axis of rotation of the base. For
example, the base may have a plane orthogonal to the base axis of
rotation that passes substantially between the upper and lower
surface of the base. The motor may have a plane orthogonal to the
motor axis of rotation that passes substantially through the center
of the motor. The base planes and motor planes may be substantially
coplanar. The motor plane may pass between the upper and lower
surface of the base.
A brushless motor assembly may include the rotor and stator. The
motor assembly may include the electronic components. The
integration of a brushless motor into the rotor assembly may reduce
the overall size of the centrifuge assembly. In some embodiments,
the motor assembly does not extend beyond the base height. In other
embodiments, the height of the motor assembly is no greater than
1.5 times the height of the base, than twice the height of the
base, than 2.5 times the height of the base, than three times the
height of the base, than four times the height of the base, or five
times the height of the base. The rotor may be surrounded by the
base such that the rotor is not exposed outside the base.
The motor assembly may effect the rotation of the centrifuge
without requiring a spindle/shaft assembly. The rotor may surround
the stator which may be electrically connected to a controller
and/or power source.
In some embodiments, the cavity may be configured to have a first
orientation when the base is at rest, and a second orientation when
the base is rotating. The first orientation may be a vertical
orientation and a second orientation may be a horizontal
orientation. The cavity may have any orientation, where the cavity
may be more than and/or equal to about 0 degrees, 5 degrees, 10
degrees, 15 degrees, 20 degrees, 25 degrees, 30 degrees, 35
degrees, 40 degrees, 45 degrees, 50 degrees, 55 degrees, 60
degrees, 65 degrees, 70 degrees, 75 degrees, 80 degrees, 85
degrees, or 90 degrees from vertical and/or the axis of rotation.
In some embodiments, the first orientation may be closer to
vertical than the second orientation. The first orientation may be
closer to parallel to the axis of rotation than the second
orientation. Alternatively, the cavity may have the same
orientation regardless of whether the base is at rest or rotating.
The orientation of the cavity may or may not depend on the speed at
which the base is rotating.
The centrifuge may be configured to accept a sample vessel, and may
be configured to have the sample vessel at a first orientation when
the base is at rest, and have the sample vessel at a second
orientation when the base is rotating. The first orientation may be
a vertical orientation and a second orientation may be a horizontal
orientation. The sample vessel may have any orientation, where the
sample vessel may be more than and/or equal to about 0 degrees, 5
degrees, 10 degrees, 15 degrees, 20 degrees, 25 degrees, 30
degrees, 35 degrees, 40 degrees, 45 degrees, 50 degrees, 55
degrees, 60 degrees, 65 degrees, 70 degrees, 75 degrees, 80
degrees, 85 degrees, or 90 degrees from vertical. In some
embodiments, the first orientation may be closer to vertical than
the second orientation. Alternatively, the sample vessel may have
the same orientation regardless of whether the base is at rest or
rotating. The orientation of the vessel may or may not depend on
the speed at which the base is rotating.
A sample may be dispensed and/or picked up from the cavity. The
sample may be dispensed and/or picked up using a fluid handling
system. The fluid handling system may be the pipette described
elsewhere herein, or any other fluid handling system known in the
art. The sample may be dispensed and/or picked up using a tip,
having any of the configurations described elsewhere herein. The
dispensing and/or aspiration of a sample may be automated.
In some embodiments, a sample vessel may be provided to or removed
from a centrifuge. The sample vessel may be inserted or removed
from the centrifuge using a device in an automated process. The
sample vessel may extend from the surface of the centrifuge, which
may simplify automated pick up and/or retrieval. A sample may
already be provided within the sample vessel. Alternatively, a
sample may be dispensed and/or picked up from the samples vessel.
The sample may be dispensed and/or picked up from the sample vessel
using the fluid handling system.
In some embodiments, a tip from the fluid handling system may be
inserted at least partially into the sample vessel and/or cavity.
The tip may be insertable and removable from the sample vessel
and/or cavity. In some embodiments the sample vessel and the tip
may be the centrifugation vessel and centrifugation tip as
previously described, or have any other vessel or tip
configuration. In some embodiments, a cuvette, such as described in
FIGS. 27A and 27B can be placed in the centrifuge rotor. This
configuration may offer certain advantages over traditional tips
and/or vessels. In some embodiments, the cuvettes may be patterned
with one or more channels with specialized geometries such that
products of the centrifugation process are automatically separated
into separate compartments. One such embodiment might be a cuvette
with a tapered channel ending in a compartment separated by a
narrow opening. The supernatant (e.g. plasma from blood) can be
forced into the compartment by centrifugal forces, while the red
blood cells remain in the main channel. The cuvette may be more
complicated with several channels and/or compartments. The channels
may be either isolated or connected.
In some embodiments, one or more cameras may be placed in the
centrifuge rotor such that it can image the contents of the
centrifuge vessel while the rotor is spinning. The camera images
may be analyzed and/or communicated in real time, such as by using
a wireless communication method. This method may be used to track
the rate of sedimentation/cell packing, such as for the ESR
(erythrocyte sedimentation rate) assay, where the speed of RBC (red
blood cell) settling is measured. In some embodiments, one or more
cameras may be positioned outside the rotor that can image the
contents of the centrifuge vessel while the rotor is spinning. This
may be achieved by using a strobed light source that is timed with
the camera and spinning rotor. Real-time imaging of the contents of
a centrifuge vessel while the rotor is spinning may allow one to
stop spinning the rotor after the centrifugation process has
completed, saving time and possibly preventing over-packing and/or
over-separation of the contents.
Referring now to FIG. 46, one embodiment of a centrifuge with a
sample imaging system will now be described. FIG. 46 shows that, in
some embodiments, the imaging device 3750 such as but not limited
to a camera, a CCD sensor, or the like may be used with a
centrifuge rotor 3800. In this example, the imaging device 3750 is
stationary while the centrifuge rotor 3800 is spinning. Imaging may
be achieved by using a strobed light source that is timed with the
camera and spinning rotor. Optionally, high speed image capture can
also be used to acquire images without the use of a strobe.
FIG. 47 shows one embodiment of the imaging device 3750 that can be
mounted in a stationary position to view the centrifuge vessel
while it is spinning in the centrifuge. FIG. 47 shows that in
addition to the imaging device 3750, illumination source(s) 3752
and 3754 may also be used to assist in image capture. The mounting
device 3756 is configured to position the imaging device 3750 to
have a field of view and focus that enables a clear view of the
centrifuge vessel and content therein.
Referring now to FIGS. 48 to 50, yet another embodiment of a
centrifuge with a sample imaging system will now be described. FIG.
48 shows that, in some embodiments, the imaging device 3770 such as
but not limited to a camera, a CCD sensor, or the like may be
mounted inside or in the same rotation frame of reference as the
centrifuge rotor 3800. FIG. 49 shows a cross-sectional view showing
that the imaging device 3770 is positioned to view into the sample
in the centrifuge vessel 3772 through an opening 3774 (shown in
FIG. 50). Because the imaging system is in the centrifuge rotor
3800, the imaging system can continuously image the centrifuge
vessel 3772 and the sample therein without the use of a strobe
illumination system. Optionally, the centrifuge rotor 3800 can be
appropriately balanced to account for the additional weight of the
imaging device 3770 in the rotor.
Thermal Control Unit
In accordance with some embodiments of the invention, a system may
include one or more thermal control unit. A device may include one
or more thermal control unit therein. For example, one or more
thermal control unit may be provided within a device housing. A
module may have one or more thermal control unit. One, two, or more
modules of a device may have a thermal control unit therein. The
thermal control unit may be supported by a module support
structure, or may be contained within a module housing. A thermal
control unit may be provided at a device level (e.g., overall
across all modules within a device), rack level (e.g., overall
across all modules within a rack), module level (e.g., within a
module), and/or component level (e.g., within one or more
components of a module).
A thermal control unit may be configured to heat and/or cool a
sample or other fluid or module temperature or temperature of the
entire device. Any discussion of controlling the temperature of a
sample may also refer to any other fluid herein, including but not
limited to reagents, diluents, dyes, or wash fluid. In some
embodiments, separate thermal control unit components may be
provided to heat and cool the sample. Alternatively, the same
thermal control unit components may both heat and cool the
sample.
The thermal control unit may be used to vary and/or maintain the
temperature of a sample to keep the sample at a desire temperature
or within a desired temperature range. In some embodiments, the
thermal control unit may be capable of maintaining the sample
within 1 degree C. of a target temperature. In other embodiments,
the thermal control unit may be capable of maintaining the sample
within 5 degrees C., 4 degrees C., 3 degrees C., 2 degrees C., 1.5
degrees C., 0.75 degrees C., 0.5 degrees C., 0.3 degrees C., 0.2
degrees C., 0.1 degrees C., 0.05 degrees C., or 0.01 degrees C. of
the target temperature. A desired target temperature may be
programmed. The desired target temperature may vary or may be
maintained over time. A target temperature profile may account for
variations in desired target temperature over time. The target
temperature profile may be provided dynamically from an external
device, such as a server, may be provided from on-board the device,
or may be entered by an operator of the device.
The thermal control unit may be able to account for temperatures
external to the device. For example, one or more temperature sensor
may determine the environmental temperature external to the device.
The thermal control unit may operate to reach a target temperature,
compensating for different external temperatures.
The target temperature may remain the same or may vary over time.
In some embodiments, the target temperature may vary in a cyclic
manner. In some embodiments, the target temperature may vary for a
while and then remain the same. In some embodiments, the target
temperature may follow a profile as known in the art for nucleic
acid amplification. The thermal control unit may control the sample
temperature to follow the profile known for nucleic acid
amplification. In some embodiments, the temperature may be in the
range of about 30-40 degrees Celsius. In some instances, the range
of temperature is about 0-100 degrees Celsius. For example, for
nucleic acid assays, temperatures up to 100 degrees Celsius can be
achieved. In an embodiment, the temperature range is about 15-50
degrees Celsius. In some embodiments, the temperature may be used
to incubate one or more sample.
The thermal control unit may be capable of varying the temperature
of one or more sample quickly. For example, the thermal control
unit may ramp the sample temperature up or down at a rate of more
than and/or equal to 1 C/min, 5 C/min, 10 C/min, 15 C/min, 30
C/min, 45 C/min, 1 C/sec, 2 C/sec, 3 C/sec, 4 C/sec, 5 C/sec, 7
C/sec, or 10 C/sec.
A thermal control unit of the system can comprise a thermoelectric
device. In some embodiments, the thermal control unit can be a
heater. A heater may provide active heating. In some embodiments,
voltage and/or current provided to the heater may be varied or
maintained to provide a desired amount of heat. A thermal control
unit may be a resistive heater. The heater may be a thermal block.
In one embodiment, a thermal block is used in a nucleic acid assay
station to regulate the temperature of reactions.
A thermal block may have one or many openings to enable
incorporation of detectors and/or light sources. Thermal blocks may
have openings for imaging of contents. Openings in thermal blocks
can be filled and/or covered to improve thermal properties of the
block.
The heater may or may not have components that provide active
cooling. In some embodiments, the heater may be in thermal
communication with a heat sink. The heat sink may be passively
cooled, and may permit heat to dissipate to the surrounding
environment. Is some embodiments, the heat sink or the heater may
be actively cooled, such as with forced fluid flow. The heat sink
may or may not contain one or more surface feature such as fins,
ridges, bumps, protrusions, grooves, channels, holes, plates, or
any other feature that may increase the surface area of the heat
sink. In some embodiments, one or more fan or pump may be used to
provide forced fluid cooling.
In some embodiments, the thermal control unit can be a Peltier
device or may incorporate a Peltier device. The thermal control
unit may optionally incorporate fluid flow to provide temperature
control. For example, one or more heated fluid or cooled fluid may
be provided to the thermal control unit. In some embodiments,
heated and/or cooled fluid may be contained within the thermal
control unit or may flow through the thermal control unit. Air
temperature control can be enhanced by the use of heat pipes to
rapidly raise temperature to a desired level. By using forced
convection, heat transfer can be made faster. Forced convective
heat transfer could also be used to thermocycle certain regions by
alternately blowing hot and cold air. Reactions requiring specific
temperatures and temperature cycling can be done on a tip and/or
vessel, where heating and cooling of the tip is finely controlled,
such as by an IR heater.
In some embodiments, a thermal control unit may use conduction,
convection and/or radiation to provide heat to, or remove heat from
a sample. In some embodiments, the thermal control unit may be in
direct physical contact with a sample or sample holder. The thermal
control unit may be in direct physical contact with a vessel, tip,
microcard, or housing for a vessel, tip, or microcard. The thermal
control unit may contact a conductive material that may be in
direct physical contact with a sample or sample holder. For
example, the thermal control unit may contact a conductive material
that may be in direct physical contact with a vessel, tip,
microcard, or a housing to support a vessel, tip, or microcard. In
some embodiments, the thermal control unit may be formed of or
include a material of high thermal conductivity. For example, the
thermal control unit may include a metal such as copper, aluminum,
silver, gold, steel, brass, iron, titanium, nickel or any
combination or alloy thereof. For example, the thermal control unit
can include a metal block. In some embodiments, the thermal control
unit may include a plastic or ceramic material.
One or more samples may be brought to and/or removed from the
thermal control unit. In some embodiments, the samples may be
brought to and/or removed from the thermal control unit using a
fluid handling system. The samples may be brought to and/or removed
from the thermal control unit using any other automated process.
The samples may be transported to and from the thermal control unit
without requiring human intervention. In some embodiments, the
samples may be manually transferred to or from the thermal control
unit.
The thermal control unit may be configured to be in thermal
communication with a sample of a small volume. For example, the
thermal control unit may be configured to be thermal communication
with a sample with a volume as described elsewhere herein.
The thermal control unit may be in thermal communication with a
plurality of samples. In some instances, the thermal control unit
may keep each of the same samples at the same temperature relative
to one another. In some instances, a thermal control unit may be
thermally connected to a heat spreader which may evenly provide
heat to the plurality of samples.
In other embodiments, the thermal control unit may provide
different amounts of heat to the plurality of samples. For example,
a first sample may be kept at a first target temperature, and a
second sample may be kept at a second target temperature. The
thermal control unit may form a temperature gradient. In some
instances, separate thermal control units may keep different
samples at different temperatures, or operating along separate
target temperature profiles. A plurality of thermal control units
may be independently operable.
One or more sensor may be provided at or near the thermal control
unit. One or more sensor may be provided at or near a sample in
thermal communication with the thermal control unit. In some
embodiments, the sensor may be a temperature sensor. Any
temperature sensor known in the art may be used including, but not
limited to thermometers, thermocouples, or IR sensors. A sensor may
provide one or more signal to a controller. Based on the signal,
the controller may send a signal to the thermal control unit to
modify (e.g., increase or decrease) or modify the temperature of
the sample. In some embodiments, the controller may directly
control the thermal control unit to modify or maintain the sample
temperature. The controller may be separate from the thermal
control unit or may be a part of the thermal control unit.
In some embodiments, the sensors may provide a signal to a
controller on a periodic basis. In some embodiments, the sensors
may provide real-time feedback to the controller. The controller
may adjust the thermal control unit on a periodic basis or in
real-time in response to the feedback.
As previously mentioned, the thermal control unit may be used for
nucleic acid amplification (e.g., isothermal and non-isothermal
nucleic acid amplification, such as PCR), incubation, evaporation
control, condensation control, achieving a desired viscosity,
separation, or any other use known in the art.
Nucleic Acid Assay Station
In some embodiments, a system, device, or module disclosed herein
may contain a nucleic acid assay station. A nucleic acid assay
station may contain one or more hardware components for
facilitating the performance of nucleic acid assays (e.g. a thermal
control unit). A nucleic acid assay station may also contain one or
more detection units or sensors for monitoring or measuring
non-nucleic acid assays (e.g. general chemistry assays,
immunoassays, etc.). A nucleic acid assay station may be
incorporated with or may be separate from a cartridge or general
assay station of a module or device. A nucleic acid assay station
may also be referred herein to as a "nucleic acid amplification
module."
FIG. 51 shows an example of a nucleic acid assay station 10201. A
nucleic acid assay station 10201 may contain a thermal block 10202.
The thermal block 10202 may be shaped to receive or support one or
more vessels 10203 (including assay units, tips, and any nucleic
acid vessel/tip disclosed elsewhere herein), such as by having
wells. The thermal block may have any of the features of a thermal
control unit described elsewhere herein. For example, the thermal
block may maintain a selected temperature or range or cycle of
temperatures in order to perform or support a nucleic acid assay
(e.g. to thermocycle for a PCR assay or to maintain a selected
constant temperature for an isothermal assay). In some embodiments,
the thermal block may be in thermal contact with a heater or
thermal control unit, such that the thermal block itself does not
contain components for regulating heat. Instead, the temperature of
the thermal block may be regulated by the temperature of the heater
or thermal control unit in thermal contact with the heating
block.
A nucleic acid assay station may be configured to receive 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35,
40, 45, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275,
300, 400, 500, or more vessels. In some embodiments, a thermal
block may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18,
20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 125,
150, 175, 200, 225, 250, 275, 300, 400, 500, or more wells. A
nucleic acid assay station may be positioned in a device or module
such that it may be accessed by a sample handling system of the
device or module. For example, a sample handling system of a device
or module may be configured to transport vessels to or from a
nucleic acid assay station.
In some embodiments, a nucleic acid assay station 10201 may contain
a movable portion 10204. The moveable portion may be configured for
movement along a guide structure of the station, such as a track
10205 or guide rod. The moveable portion may have two or more
positions, including an open position and a closed position. When
the movable portion 10204 is in an open position, the wells of a
thermal block 10202 may be accessible, so that vessels may be
placed in or removed from the thermal block (e.g. by a sample
handling system). In contrast, when the movable portion 10204 is in
a closed position, it may obstruct one or more wells of the thermal
block 10202, such that vessels cannot be placed in or removed from
the thermal block.
In some embodiments, a nucleic acid assay station may contain one
or more light sources. In some embodiments, a nucleic acid assay
station may contain the same number of light sources as number of
vessels as the station is configured to receive (e.g. if the
station is configured to receive 10 vessels, it contains 10 light
sources). The light source may be any light source disclosed
elsewhere herein, including, for example a laser or a
light-emitting diode. The light source(s) may be configured such
that it is in a fixed position relative to a thermal block or
vessel wells. A light source may be in-line with a well of the
thermal block, or it may be to the side (e.g. at a 90 degree
angle). Alternatively, the light source(s) may be movable relative
to the thermal block or other components of the nucleic acid assay
station. The light source(s) may be supported by a moveable portion
of the station. In some embodiments, when the movable portion is in
a closed position, light sources(s) supported by the movable
portion are positioned such that light from the light source(s) is
directed to the wells of a thermal block or the vessels therein. In
some embodiments, one or more components of the nucleic acid assay
station may be moveable relative to the light source.
In some embodiments, a nucleic acid assay station may contain one
or more optical sensors. In some embodiments, a nucleic acid assay
station may contain the same number of optical sensors as number of
vessels as the station is configured to receive (e.g. if the
station is configured to receive 10 vessels, it contains 10 optical
sensors). The optical sensor may be any sensor for detecting light
signals disclosed elsewhere herein, including, for example a PMT,
photodiode, or CCD sensor. The optical sensor may be configured
such that it is in a fixed position relative to a thermal block or
vessel wells. An optical sensor may be in-line with a well of the
thermal block, or it may be to the side (e.g. at a 90 degree
angle). Alternatively, the optical sensors(s) may be movable
relative to the thermal block or other components of the nucleic
acid assay station. The optical sensors (s) may be supported by a
moveable portion of the station. In some embodiments, when the
movable portion is in a closed position, optical sensors (s)
supported by the movable portion are positioned such that light
generated from or passing through the wells of a thermal block or
the vessels therein may reach the optical sensor. In some
embodiments, one or more components of the nucleic acid assay
station may be moveable relative to the optical sensor.
A nucleic acid assay station may contain both a light source and an
optical sensor. Stations containing both a light source and an
optical sensor may have capabilities similar to a
spectrophotometer. In some embodiments, a nucleic acid assay
station containing both a light source and optical sensor may be
configured to perform a measurement involving assessing an optical
property of a sample which is typically performed in a dedicated
spectrophotometer--for example, measurement of: color, absorbance,
transmittance, fluorescence, light-scattering properties, or
turbidity of a sample. In some embodiments, a nucleic acid assay
station containing both a light source and optical sensor can
perform a measurement of a sample that only uses the optical
sensor--e.g. measurement of the luminescence of a sample. In such
situations, the light source of the station may be turned off or
blocked while the optical sensor detects light emitted from the
sample. Assay types that may be measured include, for example,
nucleic acid assays, immunoassays, and general chemistry
assays.
In some embodiments, a nucleic acid assay station may contain an
optical sensor and optionally, a light source for each well of the
heating block or station. Inclusion of an optical sensor for each
well may permit the simultaneous measurement of multiple different
assays in the nucleic acid assay station at the same time.
In some embodiments, nucleic acid assay station may contain an
optical sensor at a fixed position in or adjacent to the thermal
block. The optical sensor may be in-line with the well of a thermal
block, or to the side of the well of the thermal block. There may
be an opening or a channel in the wall of the well of thermal block
creating an optical path between the interior of the well and the
optical sensor. The nucleic acid assay station may also contain a
light source. The light source may be attached to a movable portion
of the assay station, configured such that in one or more positions
of the movable portion, the light from the light source is directed
into the well of the thermal block. In situations where the light
source and the optical sensor are both in-line with the well of the
thermal block (due to the light source and optical sensor having
fixed or movable positions), various types of spectrophotometric
readings of the sample may be obtained--e.g. absorbance,
transmittance, or fluorescence. In situations where the optical
sensor is at an angle to the light source and the well of the
thermal block, spectrophotometric readings of the sample that may
be obtained include, for instance, light scattering, fluorescence,
and turbidity.
To perform fluorescence assays in a nucleic acid assay station, a
light source having a narrow emission wavelength profile may be
used (e.g. a light emitting diode). In addition or alternatively,
an excitation filter may be placed between the light source and the
sample, such that light of only a selected wavelength(s) reaches
the sample. Furthermore, an emissions filter may be placed between
the sample and the optical detector, such that only light of a
selected wavelength (typically that which is emitted by the
fluorescent compound) reaches the optical detector.
In some embodiments, a nucleic acid assay (e.g. a nucleic acid
amplification assay) may be performed or detected in a nucleic acid
assay station. Given the various optical configurations of nucleic
acid assay stations, the stations can be configured to measure
nucleic acid amplification assays which result in multiple
different types of optical changes in the reaction, such as
fluorescence or turbidity. In addition, in some embodiments, any
type of assay resulting in a change in optical properties of the
sample may be measured in a nucleic acid assay station. For
example, a non-nucleic acid assay resulting in a change of
turbidity of a sample may be measured in a nucleic acid assay
station, by measuring, for example, the absorbance of the sample or
the light scattered by the sample. In some embodiments, a nucleic
acid assay station may have certain wells of the thermal block
configured for measurement of fluorescence of samples (e.g. they
may contain filters or light sources of particular wavelengths),
and certain wells of the thermal block configured for measurement
of turbidity of samples (e.g. they may have optical sensors at an
angle to the light source and well or they may lack filters). In
some embodiments, a nucleic acid assay station may have one or more
wells that are configured for detecting nucleic acid assays, and
one or more wells that are configured for detecting non-nucleic
acid assays.
In some embodiments, assay units or other reaction vessels
described elsewhere herein may be transported to or situated in a
nucleic acid assay station described herein for measurement of the
reaction in the vessel. Accordingly, in addition to supporting
nucleic acid assays, a nucleic acid assay station may function as a
detection unit for a wide range of assays (e.g. immunoassays and
general chemistry assays). This may facilitate performing and
detecting multiple different assays simultaneously in a module or
device provided herein.
Cytometer
In accordance with some embodiments of the invention, a system may
include one or more cytometer. A device may include one or more
cytometer therein. For example, one or more cytometer may be
provided within a device housing. A module may have one or more
cytometer. One, two, or more modules of a device may have a
cytometer therein. The cytometer may be supported by a module
support structure, or may be contained within a module housing.
Alternatively, the cytometer may be provided external to the
module. In some instances, a cytometer may be provided within a
device and may be shared by multiple modules. The cytometer may
have any configuration known or later developed in the art.
In some embodiments, the cytometer may have a small volume. For
example, the cytometer may have a volume of less than or equal to
about 0.1 mm.sup.3, 0.5 mm.sup.3, 1 mm.sup.3, 3 mm.sup.3, 5
mm.sup.3, 7 mm.sup.3, 10 mm.sup.3, 15 mm.sup.3, 20 mm.sup.3, 25
mm.sup.3, 30 mm.sup.3, 40 mm.sup.3, 50 mm.sup.3, 60 mm.sup.3, 70
mm.sup.3, 80 mm.sup.3, 90 mm.sup.3, 100 mm.sup.3, 125 mm.sup.3, 150
mm.sup.3, 200 mm.sup.3, 250 mm.sup.3, 300 mm.sup.3, 500 mm.sup.3,
750 mm.sup.3, or 1 m.sup.3.
The cytometer may have a footprint of about less than or equal to
0.1 mm.sup.2, 0.5 mm.sup.2, 1 mm.sup.2, 3 mm.sup.2, 5 mm.sup.2, 7
mm.sup.2, 10 mm.sup.2, 15 mm.sup.2, 20 mm.sup.2, 25 mm.sup.2, 30
mm.sup.2, 40 mm.sup.2, 50 mm.sup.2, 60 mm.sup.2, 70 mm.sup.2, 80
mm.sup.2, 90 mm.sup.2, 100 mm.sup.2, 125 mm.sup.2, 150 mm.sup.2,
200 mm.sup.2, 250 mm.sup.2, 300 mm.sup.2, 500 mm.sup.2, 750
mm.sup.2, or 1 m.sup.2. The cytometer may have one or more
dimension (e.g., width, length, height) of less than or equal to
0.05 mm, 0.1 mm, 0.5 mm, 0.7 mm, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6
mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 15 mm, 17 mm, 20
mm, 25 mm, 30 mm, 40 mm, 50 mm, 60 mm, 70 mm, 80 mm, 100 mm, 150
mm, 200 mm, 300 mm, 500 mm, or 750 mm.
The cytometer may accept a small volume of sample or other fluid.
For example, the cytometer may accept a volume of sample of about
500 .mu.L or less, 250 .mu.L or less, 200 .mu.L or less, 175 .mu.L
or less, 150 .mu.L or less, 100 .mu.L or less, 80 .mu.L or less, 70
.mu.L or less, 60 .mu.L or less, 50 .mu.L or less, 30 .mu.L or
less, 20 .mu.L or less, 15 .mu.L or less, 10 .mu.L or less, 8 .mu.L
or less, 5 .mu.L or less, 1 .mu.L or less, 500 nL or less, 300 nL
or less, 100 nL or less, 50 nL or less, 10 nL or less, 1 nL or
less, 500 pL or less, 250 pL or less, 100 pL or less, 50 pL or
less, 10 pL or less, 5 pL or less, or 1 pL or less.
The cytometer may utilize one or more illumination techniques,
including but not limited to bright field, dark field, forward
illumination, oblique illumination, back illumination, phase
contrast and differential interference contrast microscopy.
Focusing may be achieved using any of the illumination sources,
including but not limited to dark field imaging. Dark field imaging
may be performed with a various illumination sources of different
wavelength bands. Dark field imaging may be performed with a light
guide outside the objective. Images produced by the imaging system
may be monochromatic and/or color. The imaging system may be
configured to be optics free, reducing cost and size.
The cytometer (as well as other modules) can be configured to
incorporate image processing algorithms to extract quantitative
information from images of cells and other elements in the sample
to enable computation of reportables. Where employed, the image
processing and analysis may include but are not limited to: a)
image acquisition, compression/decompression and quality
improvement, b) image segmentation, c) image stitching, and d)
extraction of quantitative information.
Detection Unit
In accordance with some embodiments of the invention, a system may
include one or more detection unit. In some embodiments, a
detection station provided herein may contain a detection unit. A
device may include one or more detection unit therein. For example,
one or more detection unit may be provided within a device housing.
A module may have one or more detection unit. One, two, or more
modules of a device may have a detection unit therein. The
detection unit may be supported by a module support structure, or
may be contained within a module housing. Alternatively, the
detection unit may be provided external to the module.
The detection unit may be used to detect a signal produced by at
least one assay on the device. The detection unit may be used to
detect a signal produced at one or more sample preparation station
in a device. The detection unit may be capable of detecting a
signal produced at any stage in a sample preparation or assay of
the device.
In some embodiments, a plurality of detection units may be
provided. The plurality of detection units may operate
simultaneously and/or in sequence. The plurality of detection units
may include the same types of detection units and/or different
types of detection units. The plurality of detection units may
operate on a synchronized schedule or independently of one
another.
In some embodiments, systems, devices, or modules provided herein
may have multiple types of detection units, which may be in one or
more detection stations. For example, a system, device or module
provided herein may contain one or more, two or more, three or
more, or all four of: i) a dedicated spectrophotometer (for
example, a spectrophotometer as described in FIG. 31); ii) a light
sensor which is not specially configured to operate with a light
source (for example, a PMT or photodiode which is not part of a
spectrophotometer); iii) a camera (for example, containing a CCD or
CMOS sensor); and iv) a nucleic acid assay station containing or
operatively coupled to a light source and a light sensor, such that
it may function as a spectrophotometer. In some embodiments, a
system, device, or module provided herein may further contain a
cytometry station containing an imaging device. In some
embodiments, one, two, three, four, or all five of the above may be
integrated in a single detection station. The single detections
station may be configured to simultaneously measure multiple
different assays at the same time.
The detection unit may be above the component from which the signal
is detected, beneath the component from which the signal is
detected, to the side of the component from which the signal is
detected, or integrated into the component from which the signal is
detected, or may have different orientation in relation to the
component from which the signal is detected. For example, the
detection unit may be in communication with an assay unit. The
detection unit may be proximate to the component from which the
signal is detected, or may be remote to the component from which
the signal is detected. The detection unit may be within one or
more mm, one or more cm, one or more 10s of cm from which the
component from which the signal is detected.
The detection unit may have a fixed position, or may be movable.
The detection unit may be movable relative to a component from
which a signal is to be detected. For example, the detection unit
can be moved into communication with an assay unit or the assay
unit can be moved into communication with the detection unit. In
one example, a sensor is provided to locate an assay unit relative
to a detector when an assay is detected.
A detection unit may include one or more optical or visual sensor
or sonic or magnetic or radioactivity sensor or some combination of
these. For example, a detection unit may include microscopy, visual
inspection, via photographic film, or may include the use of
electronic detectors such as digital cameras, charge coupled
devices (CCDs), super-cooled CCD arrays, photodetector or other
detection device. An optical detector may further include
non-limiting examples include a photodiode, photomultiplier tube
(PMT), photon counting detector, or avalanche photo diode,
avalanche photodiode arrays. In some embodiments a pin diode may be
used. In some embodiments a pin diode can be coupled to an
amplifier to create a detection device with a sensitivity
comparable to a PMT. Some assays may generate luminescence as
described herein. In some embodiments fluorescence or
chemiluminescence is detected. In some embodiments a detection
assembly could include a plurality of fiber optic cables connected
as a bundle to a CCD detector or to a PMT array. The fiber optic
bundle could be constructed of discrete fibers or of many small
fibers fused together to form a solid bundle. Such solid bundles
are commercially available and easily interfaced to CCD detectors.
In some embodiments, fiber optic cables may be directly
incorporated into assay or reagent units. For example, samples or
tips as described elsewhere herein may incorporate fiber optic
cables. In some embodiments, electronic sensors for detection or
analysis (such as image processing) may be built into the pipette
or other component of the fluid handling system. In some
embodiments, a detection unit may be a PMT. In some embodiments, a
detection unit may be a photodiode. In some embodiments, a
detection unit may be a spectrophotometer. In some embodiments, a
detection unit may be a nucleic acid assay station containing or
operatively coupled to a light source and an optical sensor. In
some embodiments, a detection unit may be a camera. In some
embodiments, a detection unit may be an imaging device. In some
embodiments, a detection unit may be a cytometry station containing
a microscopy stage and an imaging device. In some embodiments, a
detection unit containing a CCD or CMOS sensor may be configured to
obtain a digital image, such as of a sample, assay unit, cuvette,
assay, the device, or the device surroundings. The digital image
may be two-dimensional or three-dimensional. The digital image may
be a single image or a collection of images, including video. In
some instances, digital imaging may be used by the device or system
for control or monitoring of the device, it surroundings, or
processes within the device.
One or more detection units may be configured to detect a
detectable signal, which can be a light signal, including but not
limited to photoluminescence, electroluminescence,
sonoluminescence, chemiluminescence, fluorescence, phosphorescence,
polarization, absorbance, turbidity or scattering. In some
embodiments, one or more label may be employed during a chemical
reaction. The label may permit the generation of a detectable
signal. Methods of detecting labels are well known to those of
skill in the art. Thus, for example, where the label is a
radioactive label, means for detection may include a scintillation
counter or photographic film as in autoradiography. Where the label
is a fluorescent label, it may be detected by exciting the
fluorochrome with the appropriate wavelength of light and detecting
the resulting fluorescence by, for example, microscopy, visual
inspection, via photographic film, by the use of electronic
detectors such as digital cameras, charge coupled devices (CCDs) or
photomultipliers and phototubes, or other detection device. In some
embodiments, imaging devices may be used, such as cameras. In some
instances, cameras may use CCDs, CMOS, may be lensless cameras
(e.g., Frankencamera), microlens-array cameras, open-source
cameras, or may use or any other visual detection technology known
or later developed in the art. Cameras may acquire non-conventional
images, e.g. holographic images, tomographic or interferometric,
Fourier-transformed spectra, which may then be interpreted with or
without the aid of computational methods. Cameras may include one
or more feature that may focus the camera during use, or may
capture images that can be later focused. In some embodiments,
imaging devices may employ 2-d imaging, 3-d imaging, and/or 4-d
imaging (incorporating changes over time). Imaging devices may
capture static images. The optical schemes used to achieve 3-D and
4-D imaging may be one or more of the several known to those
skilled in the art, e.g. structured illumination microscopy (SLM),
digital holographic microscopy (DHM), confocal microscopy, light
field microscopy etc. The static images may be captured at one or
more point in time. The imaging devices may also capture video
and/or dynamic images. The video images may be captured
continuously over one or more periods of time. An imaging device
may collect signal from an optical system which scans the sample in
arbitrary scan patterns (e.g. raster scan). In some embodiments,
the imaging device may use one or more component of the device in
capturing the image. For example, the imaging device may use a tip
and/or vessel to assist with capturing the image. The tip and/or
vessel may function as an optic to assist in capturing an
image.
Detection units may also be capable of capturing audio signals. The
audio signals may be captured in conjunction with one or more
image. Audio signals may be captured and/or associated with one or
more static image or video images. Alternatively, the audio signals
may be captured separate from the image.
In one example, a PMT may be used as a detector. In some instances,
count rates as low as 100 per second and count rates as high as
10,000,000 may be measurable. The linear response range of PMTs
(for example, the range where count rate is directly proportional
to number of photons per unit time) can be about 1000-3,000,000
counts per second. In an example, an assay has a detectable signal
on the low end of about 200-1000 counts per second and on the high
end of about 10,000-2,000,000 counts per second. In some instances
for protein biomarkers, the count rate is directly proportional to
alkaline phosphatase bound to the capture surface and also directly
proportional to the analyte concentration.
In another example, a detector may include a camera that may be
imaging in real-time. Alternatively, the camera may take snapshots
at selected time intervals or when triggered by an event.
Similarly, the camera may take video at selected time intervals or
when triggered by an event. In some embodiments, the camera may
image a plurality of samples simultaneously. Alternatively, the
camera may image a selected view, and then move on to a next
location for a different selected view.
A detection unit may have an output that is digital and generally a
one-to-one or one-to-many transformation of the detected signal,
e.g., the image intensity value is an integer proportional to a
positive power of the number of photons reaching the camera sensor
over the time of exposure. Alternatively, the detection unit may
output an analog signal. The detectable range for exemplary
detectors can be suitable to the detector being used.
The detection unit may be capable of capturing and/or imaging a
signal from anywhere along the electromagnetic spectrum. For
example, a detection unit may be capable of capturing and/or
imaging visible signals, infra-red signals, near infra-red signals,
far infra-red signals, ultraviolet signals, gamma rays, microwaves,
and/or other signals. The detection unit may be capable of
capturing acoustic waves over a large range of frequencies, e.g.
audio, ultrasound. The detection unit may be capable of measuring
magnetic fields with a wide range of magnitude.
An optical detector can also comprise a light source, such as an
electric bulb, incandescent bulb, electroluminescent lamp, laser,
laser diode, light emitting diode (LED), gas discharge lamp,
high-intensity discharge lamp, natural sunlight, chemiluminescent
light sources. Other examples of light sources as provided
elsewhere herein. The light source can illuminate a component in
order to assist with detecting the results. For example, the light
source can illuminate an assay in order to detect the results. For
example, the assay can be a fluorescence assay or an absorbance
assay, as are commonly used with nucleic acid assays. The detector
can also comprise optics to deliver the light source to the assay,
such as a lens, mirror, scanning or galvano-mirror, prisms, fiber
optics, or liquid light guides. The detector can also comprise
optics to deliver light from an assay to a detection unit. In some
embodiments, a light source can be coupled to an optical
detector/sensor which is configured primarily for the detection of
luminescent assays, in order to expand the range of types of assays
that may be detected by the optical sensor (e.g. to include
absorbance, fluorescence, turbidity, and colorimetry assays,
etc.).
An optical detection unit may be used to detect one or more optical
signal. For example, the detection unit may be used to detect a
reaction providing luminescence. The detection unit may be used to
detect a reaction providing fluorescence, chemiluminescence,
photoluminescence, electroluminescence, color change,
sonoluminescence, absorbance, turbidity, or polarization. The
detection unit may be able to detect optical signals relating to
color intensity and phase or spatial or temporal gradients thereof.
For example, the detection unit may be configured to detect
selected wavelengths or ranges of wavelengths. The optical
detection unit may be configured to move over the sample and a
mirror could be used to scan the sample simultaneously.
In some embodiments, an assay provided herein generating a
particular type of result (e.g. luminescence, turbidity, color
change/colorimetry, etc.) may be monitored by different types or
configurations of detection units provided herein. For example, in
some situations, an assay resulting in a turbid reaction product
may be monitored in: i) a dedicated spectrophotometer, ii) a
nucleic acid assay station containing or operatively coupled to a
light source and a optical sensor, or iii) a detection unit
containing a CCD sensor (e.g. a stand-alone imaging device
containing a CCD sensor, or a cytometry station containing an
imaging device containing a CCD sensor). In both detection unit
configurations i) and ii), the sample may be positioned in the
detection unit between the respective light source and the
respective optical sensor, such that I.sub.0 (incident radiation)
and I.sub.1 (transmitted radiation) values may be measured at one
or more selected wavelengths, and absorbance calculated. In
detection unit configuration iii), an image of the sample may be
obtained by the CCD sensor, and further processed by image
analysis. In some embodiments, a sample may be monitored in more
than one of the above detection units. In another example, in some
situations, an assay resulting in a chemiluminescent signal may be
monitored by i) a photodiode or other luminescence sensor, ii) a
nucleic acid assay station containing or operatively coupled to a
light source and an optical sensor, or iii) a detection unit
containing a CCD sensor. In configuration i) the photodiode detects
light from the chemiluminescent reaction. In some situations, the
photodiode may be configured to sense very low levels of light, and
thus may be used with assays which result in only a low level of
chemiluminescence. In configuration ii) the assay (including
non-nucleic acid amplification assays) may be placed in the nucleic
acid amplification module, and the optical sensor within the
station may be used to detect light from the chemiluminescent assay
(without using the light source in the station). In some
situations, the optical sensor in this configuration may not be as
sensitive to light as a stand-alone photodiode or PMT, and
therefore, use of the nucleic acid assay station as detector for
chemiluminescence assays may be with assays which produce
relatively moderate to high levels of chemiluminescent light. In
configuration iii), an image of the chemiluminescent sample may be
obtained by the CCD sensor, and further processed by image analysis
(including light counts) to determine the level of
chemiluminescence in the sample.
In some embodiments, the controller of a system, device, or module
provided herein may be configured to select a particular detection
unit from two or more detection units within a device or module for
the detection of a signal or data from a selected assay unit within
the same device or module. For example, a module of a device
provided herein may contain three detection units: i) a photodiode,
ii) a nucleic acid assay station containing or operatively coupled
to a light source and an optical sensor, and iii) a detection unit
containing a CCD sensor. The module may also contain multiple assay
units and may simultaneously perform multiple assays. Before,
during, or after the performance of, for example, a
chemiluminescent assay in a particular movable assay unit in an
assay station in the module, the controller may determine which of
the three detection units in the module to use for receiving the
selected assay unit and detecting a signal or data from the assay
unit. In making the determination, the controller may take into
account one or more factors, such as: i) detection unit
availability--one or more of the detection units may be occupied
with other assay units at the time of the completion of the assay
in the selected assay unit; ii) detection unit suitability for
receiving a particular assay unit configuration--different
detection units may be optimized for receiving assay units of
particular shapes or sizes; iii) detection unit suitability for
detecting the signal or data from the particular assay being
performed within the selected assay unit--different detection units
may be optimized to measure a particular property of a sample (e.g.
absorbance vs. fluorescence vs. color, etc.), or different
detection units may be optimized to measure certain
features/versions of a particular property of a sample (e.g. a
detection unit containing an optical sensor may be optimized to
measure high levels of light or low levels of light, or a detection
unit configured for measuring fluorescence may be configured to
measure the fluorescence of compounds having a certain range of
excitation wavelengths and a certain range of emission
wavelengths); and iv) total time for multiplexing of assays--in
order to reduce the total time necessary to perform or obtain data
from multiple assays within the device or module, the controller
may take into account other assays simultaneously being performed
in the device or module, such that the use of each detection unit
is optimized for the combination of all assays being simultaneously
performed in the module or device. Based on the various
determinations by the controller, the controller may direct a
sample handling apparatus (for example, a pipette) within the
module to transport the assay unit containing the chemiluminescent
assay to a particular detection unit within the module, for
measurement of the chemiluminescent signal. In this example, if the
chemiluminescent assay in the selected assay unit is expected to
generate a low level of light and the photodiode is available at
the time of the completion of the assay in the selected assay unit,
the controller may direct the sample handling apparatus to
transport the selected assay unit to the photodiode for
measurement. In some embodiments, the controller may contain a
protocol for the detection of an assay in a selected assay unit
with a detection unit selected from two or more detection units in
the module or device, where the protocol takes into account one or
more of the factors indicated above relevant to the selection of a
detection unit from two or more detection units. The protocol may
be stored in the module or the device, stored in an external device
or cloud, or generated on demand. Protocols that are generated on
demand may be generated on the device or on an external device or
cloud, and downloaded to the sample processing device.
In some embodiments, the device or controller may receive or store
a protocol which contains instructions for directing a sample
handling apparatus within a device or module to move assay units to
different detection units (or vice versa) in the device or module,
and which takes into account multiple assays being simultaneously
performed in the same module or device. Optionally, with such
protocols, different assays having the same reaction outcome may be
measured in different detection units provided herein (e.g. a
chemiluminescent reaction may be measured in, for example, a PMT or
a camera containing a CCD sensor), depending on the other assays
being performed simultaneously in the same module or device. These
features of the controller, protocols, and detection units provide
multiple benefits, including, for example, the ability to
efficiently multiplex discrete assays within a device or module,
and the ability to efficiently obtain data from assays using
different detection units.
In some embodiments, the detection system may comprise optical or
non-optical detectors or sensors for detecting a particular
parameter of a subject. Such sensors may include sensors for
temperature, electrical signals, for compounds that are oxidized or
reduced, for example, O.sub.2, H.sub.2O.sub.2, and I.sub.2, or
oxidizable/reducible organic compounds. Detection system may
include sensors which measure acoustic waves, changes in acoustic
pressure and acoustic velocity. In some embodiments, systems and
devices provided herein may contain a barometer or other device for
sensing atmospheric pressure. Atmospheric pressure measurements may
be useful, for example, for adjusting protocols to high or
low-pressure situations. For example, atmospheric pressure may be
relevant to assays that measure one or more dissolved gases in a
sample. In addition, atmospheric pressure measurements may be
useful, for example, when using a device provided herein in high or
low pressure environment (e.g. at high altitudes, on an airplane,
or in space).
Examples of temperature sensors may include thermometers,
thermocouples, or IR sensors. The temperature sensors may or may
not use thermal imaging. The temperature sensor may or may not
contact the item whose temperature is to be sensed.
Examples of sensors for electrical properties may include sensors
that can detect or measure voltage level, current level,
conductivity, impedance, or resistance. Electrical property sensors
may also include potentiometers or amperometric sensors.
In some embodiments, labels may be selected to be detectable by a
detection unit. The labels may be selected to be selectively
detected by a detection unit. Examples of labels are discussed in
greater detail elsewhere herein.
Any of the sensors may be triggered according to one or more
schedule, or a detected event. In some embodiments, a sensor may be
triggered when it receives instructions from one or more
controller. A sensor may be continuously sensing and may indicate
when a condition is sensed.
The one or more sensors may provide signals indicative of measured
properties to a controller. The one or more sensors may provide
signals to the same controller or to different controllers. In some
embodiments, the controller may have a hardware and/or software
module which may process the sensor signal to interpret it for the
controller. In some embodiments, the signals may be provided to the
controller via a wired connection, or may be provided wirelessly.
The controller may be provided on a system-wide level, group of
device level, device level, module level, or component of module
level, or any other level as described elsewhere herein.
The controller may, based on the signals from the sensors, effect a
change in a component or maintain the state of a unit. For example,
the controller may change the temperature of a thermal control
unit, modify the rotation speed of a centrifuge, determine a
protocol to run on a particular assay sample, move a vessel and/or
tip, or dispense and/or aspirate a sample. In some embodiments,
based on the signals from the sensors, the controller may maintain
one or more condition of the device. One or more signal from the
sensors may also permit the controller to determine the current
state of the device and track what actions have occurred, or are in
progress. This may or may not affect the future actions to be
performed by the device. In some instances, the sensors (e.g.,
cameras) may be useful for detecting conditions that may include
errors or malfunctions of the device. The sensors may detect
conditions that may lead to an error or malfunction in data
collection. Sensors may be useful in providing feedback in trying
to correct a detected error or malfunction.
In some embodiments, one or more signal from a single sensor may be
considered for particular actions or conditions of the device.
Alternatively, one or more signals from a plurality of sensors may
be considered for particular actions or conditions of the device.
The one or more signals may be assessed based on the moment they
are provided. Alternatively, the one or more signals may be
assessed based on information collected over time. In some
embodiments, the controller may have a hardware and/or software
module which may process one more sensor signals in a
mutually-dependent or independent manner to interpret the signals
for the controller.
In some embodiments, multiple types of sensors or detection units
may be useful for measuring the same property. In some instances,
multiple types of sensors or detection units may be used for
measuring the same property and may provide a way of verifying a
measured property or as a coarse first measurement which can then
be used to refine the second measurement. For example, both a
camera and a spectroscope or other type of sensor may be used to
provide a colorimetric readout. Nucleic acid assay may be viewed
via fluorescence and another type of sensor. Cell concentration can
be measured with low sensitivity using absorbance or fluorescence
with the aim of configuring the same or another detector prior to
performing high sensitivity cytometry. With systems, devices,
methods, and assays provided herein, turbidity of a sample may be
assayed, for example, by measuring i) the light transmitted through
the sample (similar to an absorbance measurement and may include
colorimetry; the light path may travel through the sample
horizontally or vertically); or ii) the light scattered by the
sample (sometimes known as a nephelometric measurement). Typically,
for option i), the light sensor is located in-line with the light
source, and the sample to be measured is located between the light
source and the optical sensor. Typically, for option ii), the
optical sensor is offset from path of the light from the light
source (e.g. at a 90 degree angle), and the sample to be measured
is located in the path of the light source. In another example,
agglutination of a sample may be assayed, for example, by: i)
measuring the light transmitted through the sample (similar to an
absorbance measurement and may include colorimetry); ii) measuring
light scattered by the sample (sometimes known as a nephelometric
measurement); iii) obtaining an electronic image of the sample
(e.g. with a CCD or CMOS optical sensor), followed by manual or
automated image analysis; or iv) visual inspection of the
sample.
The controller may also provide information to an external device.
For example, the controller may provide an assay reading to an
external device which may further analyze the results. The
controller may provide the signals provided by the sensors to the
external device. The controller may pass on such data as raw data
as collected from the sensors. Alternatively, the controller may
process and/or pre-process the signals from the sensors before
providing them to the external device. The controller may or may
not perform any analysis on the signals received from the sensors.
In one example the controller may put the signals into a desired
format without performing any analysis.
In some embodiments, detection units may be provided inside a
housing of the device. In some instances, one or more detection
units, such as sensors may be provided external to the housing of
the device. In some embodiments, a device may be capable of imaging
externally. For example, the device may be capable of performing
MRI, ultrasound, or other scans. This may or may not utilize
sensors external to the device. In some instances, it may utilize
peripherals, which may communicate with the device. In one example
a peripheral may be an ultrasonic scanner. The peripherals may
communicate with the device through a wireless and/or wired
connection. The device and/or peripherals may be brought into close
proximity (e.g., within 1 m, 0.5 m, 0.3 m, 0.2 m, 0.1 cm, 8 cm, 6
cm, 5 cm, 4 cm, 3 cm, 2 cm, 1 cm, 0.5 cm) or contact the area to be
scanned. In some embodiments, a device may contain or communicate
with a peripheral device for performing x-rays (e.g. x-ray
generator and detector), sonography, ultrasound, or echocardiograms
(e.g. sonographic scanners), a cooximeter, or eye scans (e.g.
optical sensor). In some embodiments, a device may contain or
communicate with an independently movable peripheral that can, with
aid of an imaging device, physically follow a subject (e.g.
throughout a room or a house), and monitor the subject. The
independently movable peripheral may, for example, monitor subjects
that require a high level of care or monitoring.
In some embodiments, a sensor may be integrated into a pill or
patch. In some embodiments, a sensor may be implantable or
injectable. Optionally, such a sensor may be a multi-analyte sensor
that is implanted/injected. All such sensors (pill, patch,
implanted/injected) could measure the multiple assay methodologies
simultaneously, sequentially, or singly and may communicate with a
cell phone or external device by way of wired, wireless, or other
communication technique. Any of these sensors may be configured to
performed one or more types of assays or obtain one or more types
of data from a subject (e.g. temperature, electrochemical, etc.).
Data from the sensors may be, for example, communicated to an
external device or a sample processing device of a system provided
herein. In some embodiments, the sensors may receive instructions
from an external device or a sample processing device regarding,
for example, when to perform a measurement or what assay to
perform.
Cameras
Cameras described herein may be charge coupled device (CCDs)
cameras, super-cooled CCD cameras, or other optical cameras. Such
cameras may be formed on chips having one or more cameras, such as
part of an array of cameras. Such cameras may include one or more
optical components, for example, for capturing light, focusing
light, polarizing light, rejecting unwanted light, minimizing
scattering, improving image quality, improving signal-to-noise. In
an example, cameras may include one or more of lenses and mirrors.
Such cameras may have color or monochromatic sensors. Such cameras
may also include electronic components such as microprocessors and
digital signal processors for one or more of the following tasks:
image compression, improvement of dynamic range using computational
methods, auto-exposure, automatic determination of optimal camera
parameters, image processing, triggering strobe light to be in sync
with the camera, in-line controller to compensate for effect of
temperature changes on camera sensor performance. Such cameras may
also include on-board memory to buffer images acquired at high
frame rates. Such cameras may include mechanical features for image
quality improvement such as a cooling system or anti-vibration
system.
Cameras may be provided at various locations of point of service
systems, devices and modules described herein. In an embodiment,
cameras are provided in modules for imaging various processing
routines, including sample preparation and assaying. This may
enable the system to detect a fault, perform quality control
assessments, perform longitudinal analysis, perform process
optimization and synchronize operation with other modules and/or
systems.
In some cases, a camera includes one or more optical elements
selected from the group consisting of a lens, a mirror, a
diffraction grating, a prism, and other components for directing
and/or manipulating light. In other cases, a camera is a lens-less
(or lensless) camera configured to operate without one or more
lenses. An example of a lens-less camera is the Frankencamera. In
an embodiment, a lens-less camera uses (or collects) reflected or
scattered light and computer processing to deduce the structure of
an object.
In an embodiment, a lens-less camera has a diameter of at most
about 10 nanometers ("nm"), at most about 100 nm, at most about 1
m, at most about 10 m, at most about 100 m, at most about 1 mm, at
most about 10 mm, at most about 100 mm, or at most about 500 mm. In
another embodiment, a lens-less camera has a diameter between about
10 nm and 1 mm, or between about 50 nm and 500 .mu.m.
Cameras provided herein are configured for rapid image capture.
System employing such cameras may provide images in a delayed
fashion, in which there is a delay from the point in which an image
is captured to the point it is displayed to a user, or in
real-time, in which there is low or no delay from the point in
which an image is captured to the point it is displayed to the
user. In some situations, cameras provided herein are configured to
operate under low or substantially low lighting conditions.
In some situations, cameras provided herein are formed of optical
waveguides configured to guide electromagnetic waves in the optical
spectrum. Such optical waveguides may be formed in an array of
optical waveguides. An optical waveguide may be a planar waveguide,
which may include one or more gratings for directing light. In some
cases, the camera may have fiber optic image bundles, image
conduits or faceplates carrying light to the camera sensor.
Cameras may be useful as detection units. Cameras may also be
useful for imaging one or more sample or portion of a sample.
Cameras may be useful for pathology. Cameras may also be useful for
detecting the concentration of one or more analyte in a sample.
Cameras may be useful for imaging movement or change of a sample
and/or analytes in a sample over time. Cameras may include video
cameras that may capture images continuously. Cameras may also
optionally capture images at one or more times (e.g., periodically,
at predetermined intervals (regular or irregular intervals), in
response to one or more detected event). For example, cameras may
be useful for capturing changes of cell morphology, concentration
and spatial distribution of entities in cells that are labeled with
contrast agents (e.g. fluorescent dyes, gold nanoparticles) and/or
movement. Cell imaging may include images captured over time, which
may be useful for analyzing cell movement and morphology changes,
and associated disease states or other conditions. Cameras may be
useful for capturing sample kinematics, dynamics, morphology, or
histology. Such images may be useful for diagnosis, prognosis,
and/or treatment of a subject. An imaging device may be a camera or
a sensor that detects and/or records electromagnetic radiation and
associated spatial and/or temporal dimensions.
Cameras may be useful for interaction of an operator of a device
with the device. The cameras may be used for communications between
a device operator and another individual. The cameras may permit
teleconferencing and/or video conferencing. The cameras may permit
a semblance of face-to-face interactions between individuals who
may be at different locations. Images of a sample or component
thereof, or an assay or reaction involving same, may be stored,
enabling subsequent reflex testing, analysis and/or review. Image
processing algorithms may be used to analyze collected images
within the device or remotely.
Cameras may also be useful for biometric measurements (e.g., waist
circumference, neck circumference, arm circumference, leg
circumference, height, weight, body fat, BMI) of a subject and/or
identifying a subject or operator of a device (e.g., facial
recognition, retinal scan, fingerprint, handprint, gait, movement)
which may optionally be characterized through imaging. Embedded
imaging systems may also capture ultrasound or MRI (magnetic
resonance imaging) of a subject through the system. Cameras may
also be useful for security applications, as described elsewhere
herein. Cameras may also be useful for imaging one or more portion
of the device and for detecting error within the device. Cameras
may image and/or detect a malfunction and/or proper function of
mechanics of one or more component of the device. Cameras may be
used to capture problems, correct a problem, or learn from detected
conditions. For example, a camera may detect whether there is an
air bubble in the tip, which may end up skewing readouts or may
result in error. A camera may also be used to detect if a tip is
not properly bound to a pipette. Cameras may capture images of
components and determine whether the components are positioned
properly, or where components are positioned. Cameras may be used
as part of a feedback loop with a controller to determine the
location of components with sub-micrometer resolution and adjust
system configuration to account for the exact location.
Housing
In accordance with some embodiments of the invention, a system may
include one or more devices. A device may have a housing and/or
support structure.
In some embodiments, a device housing may entirely enclose the
device. In other embodiments, the device housing may partially
enclose the device. The device housing may include one, two, three,
four, five, six or more walls that may at least partially enclose
the device. The device housing may include a bottom and/or top. The
device housing may contain one or more modules of the device within
the housing. The device housing may contain electronic and/or
mechanical components within the housing. The device housing may
contain a fluid handling system within the housing. The device
housing may contain one or more communication unit within the
housing. The device housing may contain one or more controller
unit. A device user interface and/or display may be contained
within the housing or may be disposed on a surface of the housing.
A device may or may not contain a power source, or an interface
with a power source. The power source may be provided or interfaced
within the housing, external to the housing, or incorporated within
the housing.
A device may or may not be air tight or fluid tight. A device may
or may not prevent light or other electromagnetic waves from
entering the housing from outside the device, or escaping the
housing from within the device. In some instances, individual
modules may or may not be air tight or fluid tight and/or may or
may not prevent light or other electromagnetic waves from entering
the module.
In some embodiments, the device may be supported by a support
structure. In some embodiments, the support structure may be a
device housing. In other embodiments, a support structure may
support a device from beneath the device. Alternatively, the
support structure may support a device from one or more side, or
from the top. The support structure may be integrated within the
device or between portions of the device. The support structure may
connect portions of the device. Any description of the device
housing herein may also apply to any other support structure or
vice versa.
The device housing may fully or partially enclose the entire
device. The device housing may enclose a total volume of less than
or equal to about 4 m.sup.3, 3 m.sup.3, 2.5 m.sup.3, 2 m.sup.3, 1.5
m.sup.3, 1 m.sup.3, 0.75 m.sup.3, 0.5 m.sup.3, 0.3 m.sup.3, 0.2
m.sup.3, 0.1 m.sup.3, 0.08 m.sup.3, 0.05 m.sup.3, 0.03 m.sup.3,
0.01 m.sup.3, 0.005 m.sup.3, 0.001 m.sup.3, 500 cm.sup.3, 100
cm.sup.3, 50 cm.sup.3, 10 cm.sup.3, 5 cm.sup.3, 1 cm.sup.3, 0.5
cm.sup.3, 0.1 cm.sup.3, 0.05 cm.sup.3, or 0.01 cm.sup.3. The device
may have any of the volumes described elsewhere herein.
The device and/or device housing may have a footprint covering a
lateral area of the device. In some embodiments, the device
footprint may be less than or equal to about 4 m.sup.2, 3 m.sup.2,
2.5 m.sup.2, 2 m.sup.2, 1.5 m.sup.2, 1 m.sup.2, 0.75 m.sup.2, 0.5
m.sup.2, 0.3 m.sup.2, 0.2 m.sup.2, 0.1 m.sup.2, 0.08 m.sup.2, 0.05
m.sup.2, 0.03 m.sup.2, 100 cm.sup.2, 80 cm.sup.2, 70 cm.sup.2, 60
cm.sup.2, 50 cm.sup.2, 40 cm.sup.2, 30 cm.sup.2, 20 cm.sup.2, 15
cm.sup.2, 10 cm.sup.2, 7 cm.sup.2, 5 cm.sup.2, 1 cm.sup.2, 0.5
cm.sup.2, 0.1 cm.sup.2, 0.05 cm.sup.2, or 0.01 cm.sup.2.
The device and/or device housing may have a lateral dimension
(e.g., width, length, or diameter) or a height less than or equal
to about 4 m, 3 m, 2.5 m, 2 m, 1.5 m, 1.2 m, 1 m, 80 cm, 70 cm, 60
cm, 50 cm, 40 cm, 30 cm, 25 cm, 20 cm, 15 cm, 12 cm, 10 cm, 8 cm, 5
cm, 3 cm, 2 cm, 1 cm, 0.5 cm, 0.1 cm, 0.05 cm, or 0.01 cm. The
lateral dimensions and/or height may vary from one another.
Alternatively, they may be the same. In some instances, the device
may be a tall and thin device, or may be a short and squat device.
The height to lateral dimension ratio may be greater than or equal
to 100:1, 50:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1,
3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20,
1:30, 1:50, or 1:100.
The device and/or device housing may have any shape. In some
embodiments, the device may have a lateral cross-sectional shape of
a rectangle or square. In other embodiments, the device may have a
lateral cross-sectional shape of a circle, ellipse, triangle,
trapezoid, parallelogram, pentagon, hexagon, octagon, or any other
shape. The device may have a vertical cross-sectional shape of a
circle, ellipse, triangle, rectangle, square, trapezoid,
parallelogram, pentagon, hexagon, octagon, or any other shape. The
device may or may not have a box-like shape. The device may or may
not have a flattened planar shape and/or a rounded shape.
A device housing and/or support structure may be formed of a rigid,
semi-rigid or flexible material. A device housing may be formed of
one or more materials. In some embodiments, the device housing may
include polystyrene, moldable or machinable plastic. The device
housing may include polymeric materials. Non-limiting examples of
polymeric materials include polystyrene, polycarbonate,
polypropylene, polydimethysiloxanes (PDMS), polyurethane,
polyvinylchloride (PVC), polysulfone, polymethylmethacrylate
(PMMA), acrylonitrile-butadiene-styrene (ABS), and glass. The
device housing may be an opaque material, a translucent material, a
transparent material, or may include portions that are any
combination thereof.
The device housing may be formed of a single integral piece or
multiple pieces. The device housing may comprise multiple pieces
that may be permanently affixed to one another or removably
attached to one another. In some instances, one or more connecting
features of the housing may be contained within the housing only.
Alternatively one or more connecting features of the device housing
may be external to the device housing. The device housing may be
opaque. The device housing may prevent uncontrolled light from
entering the device. The device housing may include one or more
transparent portions. The device housing may permit controlled
light to enter selected regions of the device.
The device housing may contain one or more movable portion that may
be used to accept a sample into the device. Alternatively, the
device housing may be static as a sample is provided to the device.
For example the device housing may include an opening. The device
opening may remain open or may be closable. A device opening may
directly or indirectly lead to a sample collection unit, such that
a subject may provide a sample to the device through the device
housing. In such circumstances, the sample may be provided, for
example, to a cartridge in the device. The device may include one
or more movable tray that may accept one or more sample or other
component of the device. The tray may be translatable in a
horizontal and/or vertical direction. The opening may be in fluid
communication with one or more portion of the fluid handling system
therein. The opening may be selectively opened and/or closed. One
or more portions of the device housing may be selectively opened
and/or closed.
In some embodiments, the device housing may be configured to accept
a cartridge, or sample collection unit. In some embodiments, the
device housing may be configured to accept or collect a sample. The
device housing may be configured to collect a sample directly from
a subject or an environment. The sample receiving location may be
configured to have an opened and a closed position, such that when
closed, the device housing may be sealed. The device housing may be
in contact with the subject or environment. Additional details
relating to sample collection may be described elsewhere
herein.
In some embodiments, the housing may surround one or more of the
racks, modules, and/or components described elsewhere herein.
Alternatively, the housing may be integrally forming one or more of
the racks, modules, and/or components described elsewhere herein.
For example, the housing may provide electricity and/or energy for
the device. The housing may power the device from an energy storage
unit, energy generation unit, and/or energy conveyance unit of the
housing. The housing may provide communications between the device
and/or an external device.
Controller
A controller may be provided at any level of the system described
herein. For example, one or more controller for a system, groups of
devices, a single device, a module, a component of the device,
and/or a portion of the component may be provided.
A system may comprise one or more controller. A controller may
provide instructions to one or more device, module of a device,
component of a device, and/or portion of a component. A controller
may receive signals that may be detected from one or more sensors.
A controller may receive a signal provided by a detection unit. A
controller may comprise a local memory or may access a remote
memory. A memory may comprise tangible computer readable media with
code, instructions, language to perform one or more steps as
described elsewhere herein. A controller may be or use a
processors.
A system wide controller may be provided external to one, two or
more device and may provide instructions to or receive signals from
the one, two or more devices. In some embodiments, the controller
may communicate with selected groups of devices. In some
embodiments the controller may communicate with one or more devices
in the same geographic location, or over different geographic
locations. In some embodiments, a system wide controller may be
provided on a server or another network device.
In accordance with another embodiment of the invention, a device
may comprise one or more controller. The controller may provide
instructions to one or more module of the device, component of a
device, and/or portion of a component. The device-level controller
may receive signals that may be detected from one or more sensors,
and/or a detection unit.
The controller may comprise a local memory or may access a remote
memory on the device. The memory may comprise tangible computer
readable media with code, instructions, language to perform one or
more steps as described elsewhere herein. A device may have a local
memory that may store one or more protocols. In some embodiments, a
controller may be provided on a cloud computing infrastructure. The
controller may be spread out across one or more hardware devices.
The memory for the controller may be provided on one or more
hardware devices. The protocols may be generated and/or stored
on-board on the device. Alternatively, the protocols may be
received from an external source, such as an external device or
controller. The protocols may be stored on a cloud computing
infrastructure, or a peer to peer infrastructure. The memory may
also store data collected from a detection unit of the device. The
data may be stored for analysis of detected signals. Some signal
processing and/or data analysis may or may not occur at the device
level. Alternatively, signal processing and/or data analysis may
occur on an external device, such as a server. The signal
processing and/or data analysis may occur using a cloud computing
infrastructure. The signal processing and/or data analysis may
occur at a different location from where the device is located, or
at the same geographic location.
The device-level controller may be provided within a device and may
provide instructions to or receive signals from the one, two or
more racks, modules, components of a module, or portions of the
components. In some embodiments, the controller may communicate
with selected groups of modules, components, or portions. In some
instances, the device-level controller may be provided within a
module communicating with the other modules. In some embodiments, a
device-level controller may be provided on a module, which may have
a master-slave relationship with other modules. A modular
controller may be insertable and/or removable from a device.
A device level-controller may receive instructions from a
system-wide controller or a controller that provides instructions
to one or more devices. The instructions may be protocols which may
be stored on a local memory of the device. Alternatively, the
instructions may be executed by the device in response to the
received instructions without requiring the instructions be stored
on the device, or only having them temporarily stored on the
device. In some embodiments, the device may only store a recently
received protocol. Alternatively, the device may store multiple
protocols and be able to refer to them at a later time.
The device may provide information related to detected signals from
a detection unit to an external source. The external source
receiving the information may or may not be the same as the source
of the protocols. The device may provide raw information about the
detected signals from the detection unit. Such information may
include assay result information. The device may provide some
processing of the collected sensor information. The device may or
may not perform analysis of the collected sensor information
locally. The information sent to the external source may or may not
include processed and/or analyzed data.
A device-level controller may instruct the device to perform as a
point of service device. A point of service device may perform one
or more action at a location remote to another location. The
device-level controller may instruct the device to directly
interface with a subject or environment. The device level
controller may permit the device to be operated by an operator of
the device who may or may not be a health care professional. The
device-level controller may instruct the device to directly receive
a sample, where some additional analysis may occur remotely.
In accordance with additional embodiment of the invention, a module
may comprise one or more controller. The controller may provide
instructions to one or more components of the module, and/or
portion of a component. The module-level controller may receive
signals that may be detected from one or more sensors, and/or a
detection unit. In some examples, each module may have one or more
controllers. Each module may have one or multiple microcontrollers.
Each module may have different operating systems that may control
each module independently. The modules may be capable of operating
independently of one another. One or more module may have one or
more microcontrollers controlling different peripherals, detection
systems, robots, movements, stations, fluid actuation, sample
actuation, or any other action within a module. In some instances,
each module may have built-in graphics capabilities for high
performance processing of images. In additional embodiments, each
module may have their own controllers and/or processors that may
permit parallel processing using a plurality of modules.
The controller may comprise a local memory or may access a remote
memory on the module. The memory may comprise tangible computer
readable media with code, instructions, language to perform one or
more steps as described elsewhere herein. A module may have a local
memory that may store one or more protocols. The protocols may be
generated and/or stored on-board on the module. Alternatively, the
protocols may be received from an external source, such as an
external module, device or controller. The memory may also store
data collected from a detection unit of the module. The data may be
stored for analysis of detected signals. Some signal processing
and/or data analysis may or may not occur at the module level.
Alternatively, signal processing and/or data analysis may occur on
the device level, or at an external device, such as a server. The
signal processing and/or data analysis may occur at a different
location from where the module is located, or at the same
geographic location.
The module-level controller may be provided within a module and may
provide instructions to or receive signals from the one, two or
more components of the module, or portions of the components. In
some embodiments, the controller may communicate with selected
groups of components, or portions. In some instances, the
module-level controller may be provided within a component
communicating with the other components. In some embodiments, a
module-level controller may be provided on a component, which may
have a master-slave relationship with other components. A modular
controller may be insertable and/or removable from a module.
A module-level controller may receive instructions from a
device-wide controller, system-wide controller or a controller that
provides instructions to one or more devices. The instructions may
be protocols which may be stored on a local memory of the module.
Alternatively, the instructions may be executed by the module in
response to the received instructions without requiring the
instructions be stored on the module, or only having them
temporarily stored on the module. In some embodiments, the module
may only store a recently received protocol. Alternatively, the
module may store multiple protocols and be able to refer to them at
a later time.
The module may provide information related to detected signals from
a detection unit to the device, or an external source. The device
or external source receiving the information may or may not be the
same as the source of the protocols. The module may provide raw
information about the detected signals from the detection unit.
Such information may include assay result information. The module
may provide some processing of the collected sensor information.
The module may or may not perform analysis of the collected sensor
information locally. The information sent to the device or external
source may or may not include processed and/or analyzed data.
A module-level controller may instruct the module to perform as a
point of service module. The module-level controller may instruct
the module to directly interface with a subject or environment. The
module level controller may permit the module to be operated by an
operator of the device who may or may not be a health care
professional.
A controller may be provided at any level of the system as
described herein (e.g., high level system, groups of devices,
device, rack, module, component, portion of component). The
controller may or may not have a memory at its level.
Alternatively, it may access and/or use a memory at any other
level. The controller may or may not communicate with additional
controllers at the same or different levels. A controller may or
may not communicate with additional controllers at levels
immediately below or above them or a plurality of levels below or
above them. A controller may communicate to receive and/or provide
instructions/protocols. A controller may communicate to receive
and/or provide collected data or information based on the data.
User Interface
A device may have a display and/or user interface. In some
situations, the user interface is provided to the subject with the
aid of the display, such as through a graphical user interface
(GUI) that may enable a subject to interact with device. Examples
of displays and/or user interfaces may include a touchscreen, video
display, LCD screen, CRT screen, plasma screen, light sources
(e.g., LEDs, OLEDs), IR LED based surfaces spanning around or
across devices, modules or other components, pixelsense based
surface, infrared cameras or other capture technology based
surfaces, projector, projected screen, holograms, keys, mouse,
button, knobs, sliding mechanisms, joystick, audio components,
voice activation, speakers, microphones, a camera (e.g., 2D, 3D
cameras), multiple cameras (e.g., may be useful for capturing
gestures and motions), glasses/contact lenses with screens
built-in, video capture, haptic interface, temperature sensor, body
sensors, body mass index sensors, motion sensors, and/or pressure
sensors. Any description herein of a display and/or user interface
may apply to any type of display and/or user interface. A display
may provide information to an operator of the device. A user
interface may provide information and/or receive information from
the operator. In some embodiments, such information may include
visual information, audio information, sensory information, thermal
information, pressure information, motion information, or any other
type of information. Sound, video, and color coded information
(such as red LEDs indicating a module is in use) may be used in
providing feedback to users using a point of service system or
information system or interfacing with a system through touch or
otherwise. In some embodiments, a user interface or other sensor of
the device may be able to detect if someone is approaching the
device, and wake up.
FIG. 20 illustrates a point of service device 5600 having a display
5601. The display is configured to provide a graphical user
interface (GUI) 5602 to a subject. The display 5601 may be a touch
display, such as a resistive-touch or capacitive-touch display. The
device 5600 is configured to communicate with a remote device 5603,
such as, for example, a personal computer, Smart phone, tablet, or
server. The device 5600 has a central processing unit (CPU) 5604,
memory 5605, communications module (or interface) 5606, and hard
drive 5607. In some embodiments, the device 5600 includes a camera
5608 (or in some cases a plurality of cameras, such as for
three-dimensional imaging) for image and video capture. The device
5600 may include a sound recorder for capturing sound. Images
and/or videos may be provided to a subject with the aid of the
display 5601. In other embodiments, the camera 5608 may be a
motion-sensing input device (e.g., Microsoft.RTM. Kinect.RTM.).
One or more sensors may be incorporated into the device and/or user
interface. The sensors may be provided on the device housing,
external to the device housing, or within the device housing. Any
of the sensor types describing elsewhere herein may be
incorporated. Some examples of sensors may include optical sensors,
temperature sensors, motion sensors, depth sensors, pressure
sensors, electrical characteristic sensors, gyroscopes or
acceleration sensors (e.g., accelerometer).
In an example, the device includes an accelerometer that detects
when the device is not disposed on an ideal surface (e.g.,
horizontal surface), such as when the device has tipped over. In
another example, the accelerometer detects when the device is being
moved. In such circumstances, the device may shutdown to prevent
damage to various components of the device. In some cases, prior to
shutting down, the device takes a picture of a predetermined area
on or around the device with the aid of a camera on the device (see
FIG. 20).
The user interface and/or sensors may be provided on a housing of
the device. They may be integrated into the housing of a device. In
some embodiments, the user interface may form an outer layer of the
housing of the device. The user interface may be visible when
viewing the device. The user interface may be selectively viewable
when operating the device.
The user interface may display information relating to the
operation of the device and/or data collected from the device. The
user interface may display information relating to a protocol that
may run on the device. The user interface may include information
relating to a protocol provided from a source external to the
device, or provided from the device. The user interface may display
information relating to a subject and/or health care access for the
subject. For example, the user interface may display information
relating to the subject identity and medical insurance for the
subject. The user interface may display information relating to
scheduling and/or processing operation of the device.
The user interface may be capable of receiving one or more input
from a user of the device. For example, the user interface may be
capable of receiving instructions about one or more assay or
procedure to be performed by the device. The user interface may
receive instructions from a user about one or more sample
processing step to occur within the device. The user interface may
receive instructions about one or more analyte to be tested
for.
The user interface may be capable of receiving information relating
to the identity of the subject. The subject identity information
may be entered by the subject or another operator of the device or
imaged or otherwise captured by the user interface itself. Such
identification may include biometric information, issued
identification cards, or other uniquely identifiable biological or
identifying features, materials, or data. The user interface may
include one or more sensors that may assist with receiving
identifying information about the subject. The user interface may
have one or more question or instructions pertaining to the
subject's identity, to which the subject may respond.
In some situations, the user interface is configured to display a
questionnaire to a subject, the questionnaire including questions
about the subject's dietary consumption, exercise, health condition
and/or mental condition (see above). The questionnaire may be a
guided questionnaire, having a plurality of questions of or related
to the subject's dietary consumption, exercise, health condition
and/or mental condition. The questionnaire may be presented to the
subject with the aid of a user interface, such as graphical user
interface (GUI), on the display of the device.
The use interface may be capable of receiving additional
information relating to the subject's condition, habits, lifestyle,
diet, exercise, sleep patterns, or any other information. The
additional information may be entered directly by the subject or
another operator of the device. The subject may be prompted by one
or more questions or instructions from the user interface and may
enter information in response. The questions or instructions may
relate to qualitative aspects of the subject's life (e.g., how the
patient is feeling). In some embodiments, the information provided
by the subject are not quantitative. In some instances, the subject
may also provide quantitative information. Information provided by
the subject may or may not pertain to one or more analyte level
within a sample from the subject. The survey may also collect
information relating to therapy and/or medications undergone or
currently taken by the subject. The user interface may prompt the
subject using a survey or similar technique. The survey may include
graphics, images, video, audio, or other media features. The survey
may or may not have a fixed set of questions and/or instructions.
The survey (e.g., the sequence and/or content of the questions) may
dynamically change depending on the subject's answers.
Identifying information about the subject and/or additional
information relating to the subject may be stored in the device
and/or transmitted to an external device or cloud computing
infrastructure. Such information may be useful in analyzing data
relating to a sample collected from the subject. Such information
may also be useful for determining whether to proceed with sample
processing.
The user interface and/or sensors may be capable of collecting
information relating to the subject or the environment. For
example, the device may collect information through a screen,
thermal sensor, optical sensor, motion sensor, depth sensor,
pressure sensor, electrical characteristic sensor, acceleration
sensor, any other type of sensor described herein or known in the
art. In one example, the optical sensor may be a multi-aperture
camera capable of collecting a plurality of images and calculating
a depth therefrom. An optical sensor may be any type of camera or
imaging device as described elsewhere herein. The optical sensor
may capture one or more static images of the subject and/or video
images of the subject.
The device may collect an image of the subject. The image may be a
2D image of the subject. The device may collect a plurality of
images of the subject that may be used to determine a 3D
representation of the subject. The device may collect a one-time
image of the subject. The device may collect images of the subject
over time. The device may collect images with any frequency. In
some embodiments, the device may continually collect images in
real-time. The device may collect a video of the subject. The
device may collect images relating to any portion of the subject
including but not limited to the subject's eye or retina, the
subject's face, the subject's hand, the subject's fingertip, the
subject's torso, and/or the subject's overall body. The images
collected of the subject may be useful for identifying the subject
and/or for diagnosis, treatment, monitoring, or prevention of a
disease for the subject. In some instances, images may be useful
for determining the subject's height, circumference, weight, or
body mass index. The device may also capture the image of a
subject's identification card, insurance card, or any other object
associated with the subject.
The device may also collect audio information of the subject. Such
audio information may include the subject's voice or the sound of
one or more biological process of the subject. For example, the
audio information may include the sound of the subject's
heartbeat.
The device may collect biometric information about a subject. For
example, the device may collect information about the subject's
body temperature. In another example, the device can collect
information about the subject's pulse rate. In some instances, the
device may scan a portion of the subject, such as the subject's
retina, fingerprint or handprint. The device may determine the
subject's weight. The device may also collect a sample from the
subject and sequence the subject's DNA or a portion thereof. The
device may also collect a sample from the subject and conduct a
proteomic analysis thereon. Such information may be used in the
operation of the device. Such information may relate to the
diagnosis or the identity of the subject. In some embodiments, the
device may collect information about the operator of the device who
may or may not be different from the subject. Such information can
be useful for verifying the identity of the operator of the
device.
In some instances, such information collected by the device may be
used to identify the subject. The subject's identity may be
verified for insurance or treatment purposes. The subject identify
may be tied to the subject's medical records. In some instances,
the data collected by the device from the subject and/or sample may
be linked to the subject's records. The subject identity may also
be tied into the subject's health insurance (or other payer)
records.
Power Source
A device may have a power source or be connected to a power source.
In some embodiments, the power source may be provided external to
the device. For example, the power may be provided from a
grid/utility. The power may be provided from an external energy
storage system or bank. The power may be provided by an external
energy generation system. In some embodiments, the device may
include a plug or other connector capable of electrically
connecting the device to the external power source. In another
example, the device may use a body's natural electrical impulses to
power the device. For example, the device may contact a subject, be
worn by the subject, and/or be ingested by the subject, who may or
may not provide some power to the device. In some embodiments, the
device may include one or more piezoelectric component that may be
movable, and capable of providing power to the device. For example,
the device may have a patch configuration configured to be placed
on a subject, so that when the subject moves and/or the patch is
flexed, power is generated and provided to the device.
A device may optionally have an internal power source. For example,
a local energy storage may be provided on the device. In one
embodiment, the local energy storage may be one or more battery or
ultracapacitor. Any battery chemistry known or later developed in
the art may be used as a power source. A battery may be a primary
or secondary (rechargeable) battery. Examples of batteries may
include, but are not limited to, zinc-carbon, zinc-chloride,
alkaline, oxy-nickel hydroxide, lithium, mercury oxide, zinc-air,
silver oxide, NiCd, lead acid, NiMH, NiZn, or lithium ion. The
internal power source may be stand alone or may be coupled with an
external power source. In some embodiments, a device may include an
energy generator. The energy generator may be provided on its own
or may be coupled with an external and/or internal power source.
The energy generator may be a traditional electricity generator as
known in the art. In some embodiments, the energy generator may use
a renewable energy source including, but not limited to,
photovoltaics, solar thermal energy, wind energy, hydraulic energy,
or geothermal energy. In some embodiments, the power may be
generated through nuclear energy or through nuclear fusion.
Each device may be connected to or have a power source. Each module
may be connected to or have its own local power source. In some
instances, modules may be connected to a power source of the
device. In some instances, each module may have its own local power
source and may be capable of operating independently of other
modules and/or devices. In some instances, the modules may be able
to share resources. For example, if a power source in one of the
modules is damaged or impaired, the module may be able to access
the power source of another module or of the device. In another
example, if a particular module is consuming a larger amount of
power, the module may be able to tap into the power source of
another module or of the device.
Optionally, device components may have a power source. Any
discussion herein relating to power sources of modules and/or
devices may also relate to power sources at other levels, such as
systems, groups of devices, racks, device components, or portions
of device components.
Communication Unit
A device may have a communication unit. The device may be capable
of communication with an external device using the communication
unit. In some instances, the external device may be one or more
fellow devices. The external device may be a cloud computing
infrastructure, part of a cloud computing infrastructure, or may
interact with a cloud computing infrastructure. In some instances,
the external device that the device may communicate with may be a
server or other device as described elsewhere herein.
The communication unit may permit wireless communication between
the device and the external device. Alternatively, the
communication unit may provide wired communication between the
device and the external device. The communication unit may be
capable of transmitting and/or receiving information wirelessly
from an external device. The communication unit may permit one way
and/or two-way communication between the device and one or more
external device. In some embodiments, the communication unit may
transmit information collected or determined by the device to an
external device. In some embodiments, the communication unit may be
receiving a protocol or one or more instructions from the external
device. The device may be able to communicate with selected
external devices, or may be able to communicate freely with a wide
variety of external devices.
In some embodiments, the communication unit may permit the device
to communicate over a network, such as a local area network (LAN)
or wide area network (WAN) such as the Internet. In some
embodiments, the device may communicate via a telecommunications
network, such as a cellular or satellite network.
Some examples of technologies that may be used by a communication
unit may include Bluetooth or RTM technology. Alternatively,
various communication methods may be used, such as a dial-up wired
connection with a modem, a direct link such as TI, ISDN, or cable
line. In some embodiments, a wireless connection may be using
exemplary wireless networks such as cellular, satellite, or pager
networks, GPRS, or a local data transport system such as Ethernet
or token ring over a LAN. In some embodiments, the communication
unit may contain a wireless infrared communication component for
sending and receiving information.
In some embodiments, the information may be encrypted before it is
transmitted over a network, such as a wireless network. In some
embodiments, the encryption may be hardware-based encryption. In
some instances, the information may be encrypted on the hardware.
Any or all information, which may include user data, subject data,
test results, identifier information, diagnostic information, or
any other type of information, may be encrypted based on hardware
based and/or software based encryption. Encryption may also
optionally be based on subject-specific information. For example, a
subject may have a sample being processed by the device, and the
subject's password may be used to encrypt the data relating to the
subject's sample. By encrypting the subject's data with
subject-specific information, only the subject may be able to
retrieve that data. For example, the decryption may only occur if
the subject enters a password on a website. In another example,
information transmitted by the device may be encrypted by
information specific to the operator of the device at that time,
and may only be retrieved if the operator enters the operator's
password or provide the operator specific-information.
Each device may have a communication unit. Each module may have its
own local communication unit. In some instances, modules may share
a communication unit with the device. In some instances, each
module may have its own local communication unit and may be capable
of communicating independently of other modules and/or devices. The
module may use its communication unit to communicate with an
external device, with the device, or with other modules. In some
instances, the modules may be able to share resources. For example,
if a communication unit in one of the modules is damaged or
impaired, the module may be able to access the communication unit
of another module or of the device. In some instances, devices,
racks, modules, components or portions of device components may be
able to share one or more routers. The various levels and/or
components in the hierarchy may be able to communicate with one
another.
Optionally, device components may have a communication unit. Any
discussion herein relating to communication units of modules and/or
devices may also relate to communication units at other levels,
such as systems, groups of devices, racks, device components, or
portions of device components.
Device, Module and Component Identifier
A device may have a device identifier. A device identifier may
identify the device. In some embodiments, the device identifier may
be unique per device. In other embodiments, the device identifier
may identify a type of device, or modules/components provided
within the device. The device identifier may indicate functions
that the device is capable of performing. The device identifier may
or may not be unique in such situations.
The device identifier may be a physical object formed on the
device. For example, the device identifier may be read by an
optical scanner, or an imaging device, such as a camera. The device
identifier may be read by one or more types of sensors described
elsewhere herein. In one example, the device identifier may be a
barcode. A barcode may be a 1D or 2D barcode. In some embodiments,
the device identifier may emit one or more signal that may identify
the device. For example, the device identifier may provide an
infrared, thermal, ultrasonic, optical, audio, electrical,
chemical, biological, or other signal that may indicate the device
identity. The device identifier may use a radiofrequency
identification (RFID) tag.
The device identifier may be stored in a memory of the device. In
one example, the device identifier may be a computer readable
medium. The device identifier may be communicated wirelessly or via
a wired connection.
The device identifier may be static or changeable. The device
identifier may change as one or more module provided for the device
may change. The device identifier may change based on available
components of the device. The device identifier may change when
instructed by an operator of the device.
The device identifier may be provided to permit the device to be
integrated within a systemwide communication. For example, an
external device may communicate with a plurality of devices. The
external device may distinguish a diagnostic device from another
diagnostic device via the device identifier. The external device
may provide specialized instructions to a diagnostic device based
on its identifier. The external device may include a memory or may
communicate with a memory that may keep track of information about
the various devices. The device identifier of a device may be
linked in memory with the information collected from the device or
associated with the device.
In some embodiments, an identifier may be provided on a module or
at component level to uniquely identify each component in a device
at the system level. For example, various modules may have module
identifiers. The module identifier may or may not be unique per
module. The module identifier may have one or more characteristics
of a device identifier.
The module identifier may permit a device or system (e.g., external
device, server) to identify the modules that are provided therein.
For example, the module identifier may identify the type of module,
and may permit the device to automatically detect the components
and capability provided by the module. In some instances, the
module identifier may uniquely identify the module, and the device
may be able to track specific information associated with the
particular module. For example, the device may be able to track the
age of the module and estimate when certain components may need to
be renewed or replaced. The module may communicate with a processor
of the device which it is a part of.
Alternatively, the module may communicate with a processor of an
external device. The module identifier may provide the same
information on a system-wide level. In some embodiments, the
system, rather than the device, may track the information
associated with the module identifier.
The module identifier may be communicated to the device or system
when it is connected to the device or interfaced with a device. For
instance, the module identifier may be communicated to the device
or system after the module has been mounted on a support structure.
Alternatively, the module identifier may be communicated remotely
when the module is not yet connected to the device.
An identifier may be provided at any other level described herein
(e.g., external device, groups of devices, racks, components of a
device, portions of a component). Any characteristics of
identifiers provided herein may also apply to such identifiers.
Systems
FIG. 1 shows an example of a device 100 in communication with a
controller 110 in accordance with an embodiment of the
invention.
The device may have any of the characteristics, structure, or
functionality as described elsewhere herein. For example, the
device 100 may comprise one or more support structure 120. In some
embodiments, the support structure may be a rack, or any other
support as described elsewhere herein. In some instances, the
device may include a single support structure. Alternatively, the
device may include a plurality of support structures. A plurality
of support structure may or may not be connected to one
another.
The device 100 may comprise one or more module 130. In some
instances, a support structure 120 may comprise one or more module.
In one example, the module may have a blade format that may be
mounted on a rack support structure. Any number of modules may be
provided per device or support structure. Different support
structure may have different numbers or types of modules.
The device 100 may comprise one or more component 140. In some
instances, a module 130 may comprise one or more component of the
module. A rack 120 may comprise one or more component of a module.
Any number of components may be provided per device, rack, or
module. Different modules may have different numbers or types of
components.
In some examples, the devices may be a benchtop device, a handheld
device, a wearable device, an ingestible device, an implantable
device, a patch, and/or a pill. The device may be portable. The
device may be placed on top of a surface, such as a counter, table,
floor or any other surface. The device may be mountable or
attachable to a wall, ceiling, ground and/or any other structure.
The device may be worn directly by the subject, or may be
incorporated into the subject's clothing.
The device may be self-contained. For example, the device may
comprise a local memory. The local memory may be provided to the
overall device, or may be provided to one or more module, or may be
distributed over one or more module. The local memory may be
contained within a housing of the device. A local memory may be
provided on a support of a module or within a housing of a module.
Alternatively, the local memory of the device may be provided
external to a module while within the device housing. The local
memory of the device may or may not be supported by a support
structure of the device. The local memory may be provided external
to the support structure of the device, or may be integrated within
the support structure of the device.
One or more protocols may be stored in a local memory. One or more
protocols may be delivered to the local memory. The local memory
may include a database of information for on board analysis of
detected signals. Alternatively, the local memory may store the
information related to the detected signals that may be provided to
an external device for remote analysis. The local memory may
include some signal processing of the detected signals, but may be
transmitted to the external device for analysis. The external
device may or may not be the same device the controller.
The local memory may be capable of storing non-transitory computer
readable media, which may include code, logic, or instructions
capable of performing steps described herein.
The device may comprise a local processor. The processor may be
capable of receiving instructions and providing signals to execute
the instructions. The processor may be a central processing unit
(CPU) that may carry out instructions of tangible computer readable
media. In some embodiments, the processor may include one or more
microprocessors. The processor may be capable of communicating with
one or more component of the device, and effecting the operation of
the device.
The processor may be provided to the overall device, or may be
provided to one or more module, or may be distributed over one or
more module. The processor may be contained within a housing of the
device. A processor may be provided on a support of a module or
within a housing of a module. Alternatively, the processor of the
device may be provided external to a module while within the device
housing. The processor of the device may or may not be supported by
a support structure of the device. The processor may be provided
external to the support structure of the device, or may be
integrated within the support structure of the device.
A controller 110 may be in communication with the device 100. In
some embodiments, the controller may be a system-wide controller.
The controller may communicate with any device. The controller may
be selectively in communication with a group of devices. For
example, the system may comprise, one, two or more controller,
wherein a controller may be devoted to a group of devices. The
controller may be capable of individually communicating with each
device. In some instances, the controller may communicate with
groups of devices, without differentiating between the devices
within the group. The controller may communicate with any
combination of devices or groups of devices.
A controller may be provided external to the device. The controller
may be an external device in communication with the device. As
described elsewhere herein, an external device may be any sort of
network device. For example the controller may be a server, a
mobile device, or another diagnostic device which may have a
master-slave relationship with the device.
In alternate embodiments, the controller may be provided locally to
the device. In such situations, the device may be entirely
self-contained without requiring external communication.
The controller may comprise a memory or may communicate with a
memory. One or more protocols may be stored on the controller
memory. These protocols may be stored external to the device. The
protocols may be stored in a memory and/or cloud computing
infrastructure. The protocols may be updated on the controller side
without having to modify the device. The controller memory may
include a database of information relating to devices, samples,
subjects, and/or information collected from the devices. The
information collected from the devices may include raw data of
detected signals within the device. The information collected from
the devices may include some signal processing of the detected
signals. Alternatively, the information collected from the devices
may include analysis that may have been performed on board the
device.
The controller memory may be capable of storing non-transitory
computer readable media, which may include code, logic, or
instructions capable of performing steps described herein.
The controller may comprise a processor. The processor may be
capable of receiving instructions and providing signals to execute
the instructions. The processor may be a central processing unit
(CPU) that may carry out instructions of tangible computer readable
media. In some embodiments, the processor may include one or more
microprocessors. The processor of the controller may be capable of
analyzing data received from the devices. The processor of the
controller may also be capable of selecting one or more protocol to
provide to the device.
In some embodiments, the controller may be provided on a single
external device. The single external device may be capable of
providing protocols to the diagnostic device and/or receiving
information collected from the diagnostic device. In some
instances, the controller may be provided over a plurality of
devices. In one example, a single external device or multiple
external devices may be capable of providing protocols to the
diagnostic device. A single external device or multiple external
devices may be capable of receiving information collected from the
diagnostic device. A single external device or multiple external
devices may be capable of analyzing the information collected from
the diagnostic device.
Alternatively, the system may use cloud computing. One or more
functions of the controller may be provided by a computer network,
rather than being limited to a single external device. In some
embodiments, a network or plurality of external devices may
communicate with the diagnostic device and provide instructions to,
or receive information from the diagnostic device. Multiple
processors and storage devices may be used to perform the functions
of the controller. The controller may be provided in an environment
enabling convenient, on-demand network access to a shared pool of
configurable computing resources (e.g., networks, servers, storage,
applications, and services) that can be rapidly provisioned and
released with minimal management effort or service provider
interaction.
Communication may be provided between a diagnostic device and a
controller. The communication may be one way communication. For
example, the controller may push down a protocol to the device. In
another example, the device may initiate a request for a protocol
from the controller. Or the device may only provide information to
the controller without requiring a protocol from the
controller.
Preferably, two-way communication may be provided between the
diagnostic device and the controller. For example, a protocol may
be provided from a source external to the device. The protocol may
or may not be based on information provided by the device. For
example, the protocol may or may not be based on an input provided
to the device, which may somehow determine the information provided
by the device to the controller. The input may be manually
determined by an operator of the device. For example, the operator
may specify one or more tests that the operator wishes the device
to perform. In some instances, the input may be determined
automatically. For example, the tests to run may be determined
automatically based on a characteristic of the sample, which
modules are available or used, past records relating to a subject,
a schedule of anticipated tests, or any other information.
In some embodiments, the device may request specific protocols from
the controller. In some other embodiments, the device may provide
information to the controller, and the controller may select one or
more protocols to provide to the device based on that
information.
The device may provide information collected at the device based on
one or more detected signals from one or more sensors. The sensed
information may be provided to the controller. The sensed
information may or may not be collected during the operation of a
protocol. In some embodiments, the controller may provide an
additional protocol based on the information collected during the
first protocol.
The first protocol may be completed before the additional protocol
is initiated, or the additional protocol may be initiated before
the first protocol is completed, based on the information
collected.
A feedback system may be provided wherein a protocol may be
provided or altered based on information collected during a
protocol or after the completion of a protocol. One or more
protocol may run in parallel, in sequence, or in any combination
thereof. A device may perform an iterative process, which may use
instructions, actions performed based on the instructions, data
collected from the actions performed, which may optionally affect
subsequent instructions, and so forth. A protocol may cause the
device to perform one or more action, including but not limited to,
a sample collection step, sample preparation step, assay step,
and/or detection step.
Within a system, a device may be capable of communicating with one
or more entity. For example, the device may communicate with a lab
benefits manager, who may collect information from the device. The
lab benefits manager may analyze the information collected from the
device. The device may communicate with a protocol provider, who
may provide one or more instructions to the device. The protocol
provider and lab benefits manager may be the same entity, or may be
different entities. The device may optionally communicate with a
payer, such as an insurance company. The device may optionally
communicate with a health care provider. The device may communicate
directly with one or more of these entities, or may communicate
with them indirectly through another party. In one example, the
device may communicate with a lab benefits manager, who may
communicate with a payer and health care provider.
In some embodiments, the device may enable a subject to communicate
with a health care provider. In one example, the device may permit
one or more image of a subject to be taken by the device, and
provided to the subject's physician. The subject may or may not
view the physician on the device. The image of the subject may be
used to identification or diagnostic purposes. Other information
relating to the subject's identification may be used, as described
elsewhere herein. The subject may communicate with the physician in
real-time. Alternatively, the subject may view a recording provided
by the physician. The subject may advantageously be communicating
with the subject's own physician which may provide additional
comfort and/or sense of personal interaction for the subject.
Alternatively, the subject may communicate with other health care
providers, such as specialists.
In some embodiments, diagnostic devices within a system may share
resources. For example devices within a system may be communicating
with one another. The devices may be directly linked to one
another, or may communicate over a network. The devices may be
directly linked to a shared resource or may communicate over a
network with the shared resource. An example of a shared resource
may be a printer. For example, a plurality of devices may be in
communication with a single printer. Another example of a shared
resource may be a router.
A plurality of devices may share additional peripherals. For
example, a plurality of devices within a system may communicate
with a peripheral that may capture one or more physiological
parameter of a subject. For example, the devices may communicate
with a blood pressure measuring device, a scale, a pulse rate
measuring device, and ultrasound image capturing device, or any
other peripheral device. In some instances, a plurality of devices
and/or systems may communicate with a computer, mobile device,
tablet, or any other device that may be useful for interfacing with
a subject. Such external devices may be useful for collecting
information from the subject via a survey. In some embodiments, one
or more controller of a system may determine which device may be
using which peripheral at any given moment. In some embodiments, a
peripheral device may communicate with a sample processing device a
wireless connection (e.g. Bluetooth).
The system may be capable of dynamic resource allocation. In some
embodiments, the dynamic resource allocation may be system-wide or
within a group of devices. For example, a plurality of devices may
be connected to a plurality of shared resources. In one example,
devices A and B may be connected to printer X, and devices C and D
may be connected to printer Y. If a problem occurs with printer X,
devices A and B may be able to use printer Y. Devices A and B may
be able to communicate directly with printer Y. Alternatively,
devices A and B may not be able to communicate directly with
printer Y, but may be able to communicate with printer Y through
devices C and D. The same may go for routers, or other sharable
resources.
Methods
Methods for Processing Samples
In some embodiments, a single device, such as a module or a system
having one or more modules, is configured to perform one or more
routines selected from the group consisting of sample preparation,
sample assaying and sample detection. Sample preparation may
include physical processing and chemical processing. The single
device in some cases is a single module. In other cases, the single
device is a system having a plurality of modules, as described
above.
In one example, after a sample is collected, it may undergo one or
more sample preparation step. Alternatively, after the sample is
collected, it may directly go to a sample assay step. In another
example, a detection step may occur directly after the sample is
collected. In one example, the detection step may include taking an
image of the sample. The image may be a digital image and/or
video.
In another example, after a sample has undergone one or more sample
preparation step, it may go to a sample assay step. Alternatively,
it may go directly to a detection step.
After a sample has undergone one or more assay step, the sample may
proceed to a detection step. Alternatively, the sample may return
to one or more sample preparation step.
After a sample has undergone a detection step, it may be output.
Outputting may include displaying and/or transmitting data
collected during the detection step. Following detection, the
sample may undergo one or more sample preparation step or sample
assay step. In some instances, following detection, additional
sample may be collected.
After a sample has been displayed and/or transmitted, additional
sample preparation steps, sample assay steps, and/or detection
steps may be performed. In some instances, protocols may be sent to
a device in response to transmitted data, which may effect
additional steps. In some instances, protocols may be generated
on-board in response to detected signals. Analysis may occur
on-board the device or may occur remotely based on transmitted
data.
A single device may be capable of performing one or more sample
processing steps. In some embodiments, the term "processing"
encompasses one or more of preparing the sample, assaying the
sample, and detecting the sample to generate data for subsequent
analysis off-board (i.e., off the device) or on-board (i.e., on the
device). A sample processing step may include a sample preparation
procedure and/or assay, including any of those described elsewhere
herein. Sample processing may include one or more chemical
reactions and/or physical processing steps described herein. Sample
processing may include the assessment of histology, morphology,
kinematics, dynamics, and/or state of a sample, which may include
such assessment for cells or other assessment described herein. In
an embodiment, a single device is configured to one or more sample
preparation procedures selected from the group consisting of
weighing or volume measurement of the sample, centrifugation,
sample processing, separation (e.g., magnetic separation), other
processing with magnetic beads and/or nanoparticles, reagent
processing, chemical separation, physical separation, chemical
separation, incubation, anticoagulation, coagulation, removal of
parts of sample (e.g., physical removal of plasma, cells, lysate),
dispersion/dissolution of solid matter, concentration of selected
cells, dilution, heating, cooling, mixing, addition of reagent(s),
removal of interfering factors, preparation of a cell smear,
pulverization, grinding, activation, ultrasonication, micro column
processing, and/or any other type of sample preparation step known
in the art. In an example, a single module is configured to perform
multiple sample preparation procedures. In another example, a
single system, such as the system 700, is configured to perform
multiple sample preparation procedures. In another embodiment, a
single device is configured to perform 1 or more, or 2 or more, or
3 or more, or 4 or more, or 5 or more, or 10 or more assays
selected from the group consisting of immunoassay, nucleic acid
assay, receptor-based assay, cytometric assay, colorimetric assay,
enzymatic assay, electrophoretic assay, electrochemical assay,
spectroscopic assay, chromatographic assay, microscopic assay,
topographic assay, calorimetric assay, turbidimetric assay,
agglutination assay, radioisotope assay, viscometric assay,
coagulation assay, clotting time assay, protein synthesis assay,
histological assay, culture assay, osmolarity assay, and/or other
types of assays or combinations thereof. In some situations, a
single device is configured to perform multiple types of assays, at
least one of which is cytometry or agglutination. In other
situations, a single device is configured to perform multiple types
of assays, including cytometry and agglutination. In an example,
the system 700 is configured to perform cytometry with the aid of
the cytometry station 707. A single device may be configured to
perform any number of assays, including the numbers described
elsewhere herein, in areas relating to Chemistry--Routine
Chemistry, Hematology (includes cell-based assays, coagulation and
andrology), Microbiology--Bacteriology (includes "Molecular
Biology"), Chemistry--Endocrinology, Microbiology--Virology,
Diagnostic Immunology--General Immunology, Chemistry--Urinalysis,
Immunohematology--ABO Group & Rh type, Diagnostic
Immunology--Syphilis Serology, Chemistry--Toxicology,
Immunohematology--Antibody Detection (transfusion),
Immunohematology--Antibody Detection (non-transfusion),
Histocompatibility, Microbiology--Mycobacteriology,
Microbiology--Mycology, Microbiology--Parasitology,
Immunohematology--Antibody Identification,
Immunohematology--Compatibility Testing, Pathology--Histopathology,
Pathology--Oral Pathology, Pathology--Cytology, Radiobioassay, or
Clinical Cytogenetics. The single device may be configured for the
measurement of one or more or, two or more of, three or more of, or
any number of (including those described elsewhere herein):
proteins, nucleic acids (DNA, RNA, hybrids thereof, microRNA, RNAi,
EGS, Antisense), metabolites, gasses, ions, particles (which may
include crystals), small molecules and metabolites thereof,
elements, toxins, enzymes, lipids, carbohydrates, prion, formed
elements (e.g., cellular entities (e.g., whole cell, cell debris,
cell surface markers)). A single device may be capable of
performing various types of measurements, including but not limited
to imaging, spectrometry/spectroscopy, electrophoresis,
chromatography, sedimentation, centrifugation, or any others.
In some situations, the histology of a sample encompasses static
information of the sample as well as temporal change of the sample.
In an example, the sample as collected contains cells that multiply
(or divide) or metastasize after the sample is collected.
In another embodiment, a single device is configured to perform one
or more types of sample detection routines, such as those described
elsewhere herein.
In some embodiments, multi-use or multi-purpose devices are
configured to prepare and process a sample. Such devices may
include 1 or more, or 2 or more, or 3 or more, or 4 or more, or 5
or more, or 6 or more, or 7 or more, or 8 or more, or 9 or more, or
10 or more, or 20 or more, or 30 or more, or 40 or more, or 50 or
more, or 100 or more modules, either as part of a single system or
a plurality of systems in communication with one another. The
modules may be in fluid communication with one another.
Alternatively, the modules may be fluidically isolated or
hydraulically independent from one another. In such a case, a
sample transfer device may enable transferring a sample to and from
a module. Such devices may accept 1 or more, or 2 or more, or 3 or
more, or 4 or more, or 5 or more, or 6 or more, or 7 or more, or 8
or more, or 9 or more, or 10 or more, or 20 or more, or 30 or more,
or 40 or more, or 50 or more, or 100 or more samples. In an
embodiment, devices accept samples in a batch fashion (e.g., 5
samples provided to a device at once). In another embodiment,
devices accept samples in a continuous fashion. In some
embodiments, fluidically isolated or hydraulically independent
modules are hydraulically isolated from one another.
In an embodiment, samples are processed in parallel. In another
embodiment, samples are processed sequentially (or one after
another). Devices provided herein may prepare and analyze the same
sample or a plurality of different samples. In an example, devices
provided herein process the same blood, urine and/or tissue sample.
In another example, devices provided herein process different
blood, urine and/or tissue samples.
In some embodiments, devices for processing samples accept samples
of volumes of at least about 1 nanoliter (nL), or 10 nL, or 100 nL,
or 1 microliter (L), or 10 .mu.L, or 100 .mu.L, or 1 milliliter
(mL), or 10 mL, or 100 mL, or 1 liter (L), or 2 L, or 3 L, or 4 L,
or 5 L, or 6 L, or 7 L, or 8 L, or 9 L, or 10 L, or 100 L, or 1000
L. In other embodiments, devices for processing samples accept
samples of masses of at least about 1 nanogram (ng), or 10 ng, or
100 ng, or 1 microgram (.mu.g), or 10 .mu.g, or 100 .mu.g, or 1
milligram (mg), or 10 mg, or 100 mg, or 1 gram (g), or 2 g, or 3 g,
or 4 g, or 5 g, or 6 g, or 7 g, or 8 g, or 9 g, or 10 g, or 100 g,
or 1000 g.
A device may perform sample preparation, processing and/or
detection with the aid of one module or a plurality of modules. For
example, a device may prepare a sample in a first module (e.g., the
first module 701 of FIG. 7) and run (or perform) an assay on the
sample in a second (e.g., the second module 702 of FIG. 7) module
separate from the first module.
A device may accept one sample or a plurality of samples. In an
embodiment, a system accepts a single sample and prepares,
processes and/or detects the single sample. In another embodiment,
a system accepts a plurality of samples and prepares, processes
and/or detects one or more of the plurality of samples at the same
time.
In some embodiments, one or more modules of a device are
fluidically isolated or hydraulically independent from one another.
In an embodiment, the plurality of modules 701-706 of the system
700 are in fluid isolation with respect to one another. In an
example fluid isolation is provided by way of seals, such as fluid
or pressure seals. In some cases, such seals are hermetic seals. In
other embodiments, one or modules of a system are fluidically
coupled to one another.
In some situations, devices having a plurality of modules are
configured to communicate with one another. For example, a first
device having a plurality of modules, such as the device 1000, is
in communication with another device, such as a like or similar
device having a plurality of modules. In such fashion, two or more
devices may communicate with one another, such as to facilitate
resource sharing.
Processing of a biological sample may include pre-processing (e.g.,
preparation of a sample for a subsequent treatment or measurement),
processing (e.g., alteration of a sample so that it differs from
its original, or previous, state), and post-processing (e.g.,
fixing a sample, or disposing of all or a portion of a sample or
associated reagents following its measurement or use). A biological
sample may be divided into portions, such as aliquots of a blood or
urine sample, or such as slicing, mincing, or dividing a tissue
sample into two or more pieces. Processing of a biological sample,
such as blood sample, may include mixing, stirring, sonication,
homogenization, or other treatment of a sample or of a portion of
the sample. Processing of a biological sample, such as blood
sample, may include centrifugation of a sample or a portion
thereof. Processing of a biological sample, such as a blood sample,
may include providing time for components of the sample to separate
or settle, and may include filtration (e.g., passing the sample or
a portion thereof through a filter or membrane). Processing of a
biological sample, such as a blood sample, may include allowing or
causing a blood sample to coagulate. Processing of a biological
sample, such as blood sample, may include concentration of the
sample, or of a portion of the sample (e.g., by sedimentation or
centrifugation of a blood sample, or of a solution containing a
homogenate of tissue from a tissue sample, or with electromagnetic
other other beads) to provide a pellet and a supernatant.
Processing of a biological sample, such as blood sample, may
include dilution of a portion of the sample. Dilution may be of an
entire sample, or of a portion of a sample, including dilution of a
pellet or of a supernatant from sample. A biological sample may be
diluted with water, or with a saline solution, such as a buffered
saline solution. A biological sample may be diluted with a solution
which may or may not include a fixative (e.g., formaldehyde,
paraformaldehyde, or other agent which cross-links proteins). A
biological sample may be diluted with a solution such that an
osmotic gradient is produced between the surrounding solution and
the interior, or an interior compartment, of such cells, effective
that the cell volume is altered. For example, where the resulting
solution concentration following dilution is less than the
effective concentration of the interior of a cell, or of an
interior cell compartment, the volume of such a cell will increase
(i.e., the cell will swell). A biological sample may be diluted
with a solution which may or may not include an osmoticant (such
as, for example, glucose, sucrose, or other sugar; salts such as
sodium, potassium, ammonium, or other salt; or other osmotically
active compound or ingredient). In embodiments, an osmoticant may
be effective to maintain the integrity of cells in the sample, by,
for example, stabilizing or reducing possible osmotic gradients
between the surrounding solution and the interior, or an interior
compartment, of such cells. In embodiments, an osmoticant may be
effective to provide or to increase osmotic gradients between the
surrounding solution and the interior, or an interior compartment,
of such cells, effective that the cells at least partially collapse
(where the cellular interior or an interior compartment is less
concentrated than the surrounding solution), or effective that the
cells swell (where the cellular interior or an interior compartment
is more concentrated than the surrounding solution).
A biological sample may be dyed, or markers or reagents may be
added to the sample, or the sample may be otherwise prepared for
detection, visualization, or quantification of the sample, a
portion of a sample, a component part of a sample, or a portion of
a cell or structure within a sample. For example, a biological
sample may be contacted with a solution containing a dye. A dye may
stain or otherwise make visible a cell, a portion of a cell, a
component inside a cell, or a material or molecule associated with
a cell in a sample. A dye may bind to or be altered by an element,
compound, or other component of a sample; for example a dye may
change color, or otherwise alter one of more of its properties,
including its optical properties, in response to a change or
differential in the pH of a solution in which it is present; a dye
may change color, or otherwise alter one of more of its properties,
including its optical properties, in response to a change or
differential in the concentration of an element or compound (e.g.,
sodium, calcium, CO.sub.2, glucose, or other ion, element, or
compound) present in a solution in which the dye is present. For
example, a biological sample may be contacted with a solution
containing an antibody or an antibody fragment. For example, a
biological sample may be contacted with a solution that includes
particles. Particles added to a biological sample may serve as
standards (e.g., may serve as size standards, where the size or
size distribution of the particles is known, or as concentration
standards, where the number, amount, or concentration of the
particles is known), or may serve as markers (e.g., where the
particles bind or adhere to particular cells or types of cells, to
particular cell markers or cellular compartments, or where the
particles bind to all cells in a sample).
In an example, two rack-type devices like the system 700 of FIG. 7
are provided. The devices are configured to communicate with one
another, such as by way of a direct link (e.g., wired network) or
wireless link (e.g., Bluetooth, WiFi). While a first of the two
rack-type devices processes a portion of a sample (e.g., blood
aliquot), a second of the two-rack-type devices performs sample
detection on another portion of the same sample. The first
rack-type device then transmits its results to the second rack-type
device, which uploads the information to a server in network
communication with the second rack-type device but not the first
rack-type device.
Devices and methods provided herein are configured for use with
point of service systems. In an example, devices are deployable at
locations of healthcare providers (e.g., drug stores, doctors'
offices, clinics, hospitals) for sample preparation, processing
and/or detection. In some situations, devices provided herein are
configured for sample collection and preparation only, and
processing (e.g., detection) and/or diagnosis is performed at a
remote location certified by a certifying or licensing entity
(e.g., government certification).
In some embodiments, a user provides a sample to a system having
one or more modules, such as the system 700 of FIG. 7. The user
provides the sample to a sample collection module of the system. In
an embodiment, the sample collection module includes one or more of
a lancet, needle, microneedle, venous draw, scalpel, cup, swab,
wash, bucket, basket, kit, permeable matrix, or any other sample
collection mechanism or method described elsewhere herein. Next,
the system directs the sample from the sample collection module to
one or more processing modules (e.g., modules 701-706) for sample
preparation, assaying and/or detection. In an embodiment, the
sample is directed from the collection module to the one or more
processing modules with the aid of a sample handling system, such
as a pipette. Next, the sample is processed in the one or more
modules. In some situations, the sample is assayed in the one or
more modules and subsequently put through one or more detection
routines.
In some embodiments, following processing in the one or more
modules, the system communicates the results to a user or a system
(e.g., server) in communication with the system. Other systems or
users may then access the results to aid in treating or diagnosing
a subject.
In an embodiment, the system is configured for two-way
communication with other systems, such as similar or like systems
(e.g., a rack, such as that described in the context of FIG. 7) or
other computers systems, including servers.
Devices and methods provided herein, by enabling parallel
processing, may advantageously decrease the energy or carbon
footprint of point of service systems. In some situations, systems,
such as the system 700 of FIG. 7, has a footprint that is at most
10%, or 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or
50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or
90%, or 95%, or 99% that of other point of service systems.
In some embodiments, methods are provided for detecting analytes.
In an embodiment, a processing routine includes detecting the
presence or absence of an analyte. The processing routine is
facilitated with the aid of systems and devices provided herein. In
some situations, analytes are associated with biological processes,
physiological processes, environmental conditions, sample
conditions, disorders, or stages of disorders, such as one or more
of autoimmune disease, obesity, hypertension, diabetes, neuronal
and/or muscular degenerative diseases, cardiac diseases, and
endocrine diseases.
In some situations, a device processes one sample at a time.
However, systems provided herein are configured for multiplexing
sample processing. In an embodiment, a device processes multiple
samples at a time, or with overlapping times. In an example, a user
provides a sample to a device having a plurality of modules, such
as the system 700 of FIG. 7. The device then processes the sample
with the aid of one or more modules of the device. In another
example, a user provides multiple samples to a device having a
plurality of modules. The device then processes the samples at the
same time with the aid of the plurality of modules by processing a
first sample in a first module while processing a second sample in
second module.
The system may process the same type of sample or different types
of samples. In an embodiment, the system processes one or more
portions of the same sample at the same time. This may be useful if
various assaying and/or detection protocols on the same sample are
desired. In another embodiment, the system processes different
types of samples at the same time. In an example, the system
processes a blood and urine sample concurrently in either different
modules of the system or a single module having processing stations
for processing the blood and urine samples.
In some embodiments, a method for processing a sample with the aid
of a point of service system, such as the system 700 of FIG. 7,
comprises accepting testing criteria or parameters and determining
a test order or schedule based on the criteria. The testing
criteria is accepted from a user, a system in communication with
the point of service system, or a server. The criteria are
selectable based on a desired or predetermined effect, such as
minimizing time, cost, component use, steps, and/or energy. The
point of service system processes the sample per the test order or
schedule. In some situations, a feedback loop (coupled with
sensors) enables the point of service system to monitor the
progress of sample processing and maintain or alter the test order
or schedule. In an example, if the system detects that processing
is taking longer than the predetermined amount of time set forth in
the schedule, the system speeds up processing or adjusts any
parallel processes, such as sample processing in another module of
the system. The feedback loop permits real-time or pseudo-real time
(e.g., cached) monitoring. In some situations, the feedback loop
may provide permit reflex testing, which may cause subsequent
tests, assays, preparation steps, and/or other processes to be
initiated after starting or completing another test and/or assay or
sensing one or more parameter. Such subsequent tests, assays,
preparation steps, and/or other processes may be initiated
automatically without any human intervention. Optionally, reflex
testing is performed in response to an assay result. Namely by way
of non-limiting example, if a reflex test is ordered, a cartridge
is pre-loaded with reagents for assay A and assay B. Assay A is the
primary test, and assay B is the reflexed test. If the result of
assay A is meets a predefined criteria initiating the reflex test,
then assay B is run with the same sample in the device. The device
protocol is planned to account for the possibility of running the
reflex test. Some or all protocol steps of assay B can be performed
before the results for assay A are complete. For example, sample
preparation can be completed in advance on the device. It is
possible also to run a reflex test with a second sample from the
patient. In some embodiments, devices and systems provided herein
may contain components such that multiple different assays and
assay types may be reflex tested with the same device. In some
embodiments, multiple tests of clinical significance may be
performed in a single device provided herein as part of a reflex
testing protocol, where the performance of the same tests with
known systems and methods requires two or more separate devices.
Accordingly, systems and devices provided herein may permit, for
example, reflex testing which is faster and requires less sample
than known systems and methods. In addition, in some embodiments,
for reflex testing with a device provided herein, it is not
necessary to know in advance which reflexed tested will be
performed.
In some embodiments, the point of service system may stick to a
pre-determined test order or schedule based on initial parameters
and/or desired effects. In other embodiments, the schedule and/or
test order may be modified on the fly. The schedule and/or test
order may be modified based on one or more detected conditions, one
or more additional processes to run, one or more processes to no
longer run, one or more processes to modify, one or more
resource/component utilization modifications, one or more detected
error or alert condition, one or more unavailability of a resource
and/or component, one or more subsequent input or sample provided
by a user, external data, or any other reason.
In some examples, one or more additional samples may be provided to
a device after one or more initial samples are provided to the
device. The additional samples may be from the same subject or
different subjects. The additional samples may be the same type of
sample as the initial sample or different types of samples (e.g.,
blood, tissue). The additional samples may be provided prior to,
concurrently with, and/or subsequent to processing the one or more
initial samples on the device. The same and/or different tests or
desired criteria may be provided for the additional samples, as
opposed to one another and/or the initial samples. The additional
samples may be processed in sequence and/or in parallel with the
initial samples. The additional samples may use one or more of the
same components as the initial samples, or may use different
components. The additional samples may or may not be requested in
view of one or more detected condition of the initial samples.
In some embodiments, the system accepts a sample with the aid of a
sample collection module, such as a lancet, scalpel, or fluid
collection vessel. The system then loads or accesses a protocol for
performing one or more processing routines from a plurality of
potential processing routines. In an example, the system loads a
centrifugation protocol and cytometry protocol. In some
embodiments, the protocol may be loaded from an external device to
a sample processing device. Alternatively, the protocol may already
be on the sample processing device. The protocol may be generated
based on one or more desired criteria and/or processing routines.
In one example, generating a protocol may include generating a list
of one or more subtasks for each of the input processes. In some
embodiments, each subtask is to be performed by a single component
of the one or more devices. Generating a protocol may also include
generating the order of the list, the timing and/or allocating one
or more resources.
In an embodiment, a protocol provides processing details or
specifications that are specific to a sample or a component in the
sample. For instance, a centrifugation protocol may include
rotational velocity and processing time that is suited to a
predetermined sample density, which enables density-dependent
separation of a sample from other material that may be present with
a desirable component of the sample.
A protocol is included in the system, such as in a protocol
repository of the system, or retrieved from another system, such as
a database, in communication with the system. In an embodiment, the
system is in one-way communication with a database server that
provides protocols to the system upon request from the system for
one or more processing protocols. In another embodiment, the system
is in two-way communication with a database server, which enables
the system to upload user-specific processing routines to the
database server for future use by the user or other users that may
have use for the user-specific processing routines.
In some cases, a processing protocol is adjustable by a user. In an
embodiment, a user may generate a processing protocol with the aid
of a protocol engine that provides the user one or more options
geared toward tailoring the protocol for a particular use. The
tailoring may occur prior to use of the protocol. In some
embodiments, the protocol may be modified or updated while the
protocol is in use.
With the aid of a protocol, a system processes a sample, which may
include preparing the sample, assaying the sample and detecting one
or more components of interest in the sample. In some cases, the
system performs data analysis with respect to the sample or a
plurality of sample after processing. In other cases, the system
performs data analysis during processing. In some embodiments, data
analysis is performed on-board--that is, on the system. In other
embodiments, data analysis is performed using a data analysis
system that is external to the system. In such a case, data is
directed to the analysis system while the sample is being processed
or following processing.
In some embodiments, a single sample from a subject provided to a
device or component thereof may be used for two or more assays. The
assays may be any assays described elsewhere herein. In some
embodiments, a sample provided to a device may be whole blood. The
whole blood may contain an anticoagulant (e.g. EDTA, Coumadins,
heparin, or others). Within the device, whole blood may be
subjected to a procedure to separate blood cells from plasma (e.g.
by centrifugation or filtration). In an alternative, a sample
containing separated blood cells and plasma may be introduced into
a device (e.g. if a whole blood sample is separated into plasma and
blood cells before insertion of the sample into the device). Whole
blood may be used for one or more assays; in such circumstance, the
whole blood may be processed (e.g. diluted) prior to the assays. A
sample containing plasma and cell-containing portions may be
further processed to prepare one or both of the portions for
assays. For example, the plasma may be removed from the cells into
a new vessel and diluted with one or more different diluents to
generate one or more different sample dilution levels. The plasma
samples (diluted or non-diluted) may be used for one or more
different assays, including, for example immunoassays, general
chemistry assays, and nucleic acid assays. In some examples, a
plasma sample from an original whole blood sample may be used for
at 1, 2, 3, 4, 5, or more immunoassays, 1, 2, 3, 4, 5, or more
general chemistry assays, and 1, 2, 3, 4, 5, or more nucleic acid
assays. In some examples, the plasma samples may be used for two or
more different assays that result in two or more different optical
properties that may be measured (for example, an assay may result
in a change in the color of the assay, a change in the absorbance
of the assay, a change in the turbidity of the assay, a change in
the fluorescence of the assay, or a change in luminescence in the
assay, etc.). In addition, the cells isolated from the same whole
blood sample described above may also be used for one or more
assays. For example, the cells may be measured by cytometry.
Cytometry assays may include any descriptions of cytometry provided
elsewhere herein, including cell imaging by microscopy and flow
cytometry. In some embodiments, cells which are centrifuged or
otherwise processed in a sub-optimal anticoagulant or other buffer,
reagent, or sample condition may still be used for cytometry. In
such circumstances, it may be advantageous to separate the cells
rapidly from the sub-optimal conditions (e.g. by centrifugation or
filtration) to minimize the time the cells are exposed to the
sub-optimal conditions. In some embodiments, cells are further
processed to separate the cells into different cell fractions or
cell types--e.g. to separate red blood cells from white blood
cells. In addition, cells may be measured by other types of assays,
such as general chemistry assays (e.g. to perform hemagglutination
assays for red blood cell typing).
In some embodiments, methods are provided for performing with a
device described herein two or more assays with a single sample
from a subject, including one or more of: 1) if the sample is whole
blood, separating the whole blood into plasma and cell portions,
and optionally, retaining some blood as whole blood; 2) dividing an
original sample of whole blood into 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 100, 200, 300, 400, 500, or
more fluidically isolated aliquots; 3) dividing an original sample
of plasma into 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35,
40, 50, 60, 70, 80, 100, 200, 300, 400, 500, or more fluidically
isolated aliquots; 4) diluting an original sample of plasma into
one or more plasma samples having different dilution levels; 5)
with plasma samples, performing at least one, two, or three assays
of each of one, two, or three types of assays, the assay types
selected from immunoassays, general chemistry assays, and nucleic
acid assays; 6) with plasma sample assays, measuring assay results
at least one, two, or three different detection units, such as,
photodiodes PMTs, electrodiodes, spectrophotometers, imaging
devices, cameras, CCD sensors, and nucleic acid assay station
containing a light source and an optical sensor; 7) separating
blood cells into white blood cell or red blood cell containing
portions; 8) with cell-containing samples, performing at least one,
two, or three assays of each of one, two, three, or four types of
assays, the assay types selected from immunoassays, general
chemistry assays, nucleic acid assays, and cytometry assays; 9)
with cytometry assays, obtaining a digital image of one or more
cells; 10) with cytometry assays, obtaining a cell count; 11) with
cytometry assays, performing flow cytometry and obtaining scatter
plots; 12) heating a sample; and 13) processing a sample with any
reagent or chemical disclosed elsewhere herein.
In some embodiments, multiple samples may include multiple types of
samples. In other instances, multiple samples may include the same
type of sample. The multiple samples may be collected from the same
subject or from different subjects. The multiple samples may be
collected at the same time or at different points in time. Any
combination of these may be provided for multiple samples.
In some embodiments, point of service systems, such as the system
700 of FIG. 7, are configured for remote treatment, such as with
the aid of audio and/or visual media coupled with a communications
system, such as a network or telephonic system. In an example, a
subject provides a sample to a point of service system, which
processes the sample to generate data is processed. Next, the
system establishes a communications link with a remote healthcare
provider who reviews the subject's data and provides a diagnosis.
The healthcare provider then aids the subject in treatment. In an
embodiment, the healthcare provider is selected by the subject.
In some embodiments, at least one of the components of the system
is constructed of polymeric materials. Non-limiting examples of
polymeric materials include polystyrene, polycarbonate,
polypropylene, polydimethysiloxanes (PDMS), polyurethane,
polyvinylchloride (PVC), polysulfone, polymethylmethacrylate
(PMMA), acrylonitrile-butadiene-styrene (ABS), and glass.
Systems and subcomponents of the systems may be manufactured by
variety of methods including, without limitation, stamping,
injection molding, embossing, casting, blow molding, machining,
welding, ultrasonic welding, and thermal bonding. In an embodiment,
a device in manufactured by injection molding, thermal bonding, and
ultrasonic welding. The subcomponents of the device may be affixed
to each other by thermal bonding, ultrasonic welding, friction
fitting (press fitting), adhesives or, in the case of certain
substrates, for example, glass, or semi-rigid and non-rigid
polymeric substrates, a natural adhesion between the two
components.
Device Calibration and/or Maintenance
In some embodiments the device may be capable of performing
on-board calibration and/or controls. The device may be capable of
performing one or more diagnostic step (e.g., preparation step
and/or assay step). If the results fall outside an expected range,
a portion of the device may be cleaned and/or replaced. The results
may also be useful for calibrating the device. On-board calibration
and/or controls may occur without requiring human intervention.
Calibration and controls may occur within a device housing. A
device may also be capable of performing on-board maintenance. If
during a calibration, operation of device, diagnostic testing, or
any other point in time a condition requiring repair and/or
maintenance of the device is detected, the device may institute one
or more automated procedures to perform said maintenance and/or
repair. Any description of maintenance may include repair,
cleaning, and/or adjustments. For example, a device may detect that
a component is loose and may automatically tighten the component.
The device may also detect that a wash or diluents level is running
low in a module and provide an alert to add more wash or diluents,
or bring over wash or diluents from another module.
The system may be configured to continue to function after the
removal and/or failure of certain modules.
Calibration and/or maintenance may occur on a periodic basis. In
some embodiments, device calibration and/or maintenance may
automatically occur at regular or irregular intervals. Device
calibration and/or maintenance may occur when one or more condition
is detected from the device. For example, if a component appears to
be faulty, the device may run a diagnostic on associated
components. Device calibration and/or maintenance may occur at the
instruction of an operator of the device. Device calibration and/or
maintenance may also occur upon automated instruction from an
external device. The calibration and quality control (QC) cartridge
is briefly described in the next paragraph. The goal of the
calibration cartridge is to enable the quantitative assessment and
adjustment of each module/detector of the device. For example, by
performing a variety of assay steps, functionality is
tested/evaluated for the pipette, gantry, centrifuge, cameras,
spectrometer, nucleic acid amplification module, thermal control
unit, and cytometer. Each measurement made during calibration
cartridge runs with reagent controls may be compared to device
requirements for precision. By way of non-limiting example, there
is a pass fail outcome for these results. If re-calibration is
required, the data generated is used to recalibrate the device
(such as the device sensors and pipettes). Recalibration ensures
that each device is accurate. Some QC can also be performed
automatically in the device without introducing a cartridge. For
example, the light sources in the device can be used to
periodically QC the optical sensors in the device. An external
device or control may maintain a device calibration schedule and/or
device maintenance schedule for a plurality of devices. Device
calibration and/or maintenance may occur on a time-based schedule
or a use-based schedule. For example, devices that are used more
frequently than others may be calibrated and/or maintained more
frequently and/or vice versa. QC data may be indexed with data
stored, for example, on the sample processing device or an external
device.
In some embodiments, a calibration protocol may be stored on a
sample processing device, or on an external device and transmitted
from the external device to the sample processing device. In some
embodiments, a sample processing device may communicate with an
external device to provide QC data to the external device. In some
embodiments, the external device may send a protocol or calibration
instructions to a sample processing device based on QC data
provided from the sample processing device to the external
device.
In some embodiments, the device may be periodically calibrated and
quality controlled. Each module, consisting of one or more hardware
units, could be calibrated periodically by utilizing a calibration
cartridge. The calibration cartridge may consist of a series of
standard fluids, which a properly calibrated system gives a known
response to. The module results to these standards could be read,
analyzed and based on deviations or absence thereof, module status
can be determined, and corrected for, if necessary. The calibration
standards could either be stored in the device or introduced
separately as a cartridge.
In some embodiments, some modules may auto-correct for any changes
in the environment. For example, temperature sensors on the pipette
may automatically trigger an adjustment in the required piston
movement, to correct for temperature fluctuations. In general,
modules where feedback regarding performance is available, may
auto-correct for any changes over time.
In some embodiments, the output measurements of the cytometer may
be calibrated to match results from predicate devices or devices
utilizing other technologies as required.
In embodiments, a device may monitor its environment, including its
internal and external environment. In embodiments, a device may
provide device environmental information to a laboratory. Device
environmental information includes, e.g., internal temperature,
external temperature, internal humidity, external humidity, time,
status of components, error codes, images from an internal camera,
images from an external camera, and other information. In some
embodiments, a device may contain a thermal sensor. In embodiments,
an internal camera may be fixed at an internal location. In
embodiments, an internal camera may be fixed at an internal
location and may be configured to rotate, scan, or otherwise
provide views of multiple areas or regions within the device. In
embodiments, an internal camera may be movable within the device;
for example, an internal camera may be mounted on a movable
element, such as a pipette, within the device. In embodiments, an
internal camera may be movable within the device and may be
configured to rotate, scan, or otherwise provide multiple views of
areas within the device from multiple locations within the device.
In embodiments, an external camera may be fixed at an external
location. In embodiments, an external camera may be fixed at an
external location and may be configured to rotate, scan, or
otherwise provide multiple views of areas outside the device. In
embodiments, an external camera may be movable on or around the
outside of the device. In embodiments, an external camera may be
movable and may be configured to rotate, scan, or otherwise provide
multiple views of areas outside the device from multiple locations
on or around the outside of the device.
Transmission of device environmental information to a laboratory is
useful for the oversight and control of the device, including being
useful for the oversight and control of the dynamic operation of
the device. Transmission of device environmental information to a
laboratory is useful for maintaining the integrity of the operation
and control of the device, quality control of the operation and
control of the device, and for reducing variation or error in the
data collection and sample processing performed by the device. For
example, transmission of temperature information to a laboratory is
useful for the oversight and control of the device, and is useful
in the analysis by the laboratory of data provided by the device to
the laboratory. For example, a device may have dedicated
temperature zones, and this information may be transmitted to a
laboratory.
In embodiments, a device may be configured to control the
temperature within the device, or within a portion of the device.
The device or portion thereof may be maintained at a single
constant temperature, or at a progression of different selected
temperatures. Such control improves the reproducibility of
measurements made within the device, may unify or provide
regularity of conditions for all samples, and reduce the
variability of measurements and data, e.g., as measured by the
coefficient of variance of multiple measurements or replicate
measurements. Such control may also affect chemistry performance in
the assay(s) and speed/kinetics of the assay reaction. Temperature
information may be useful for quality control. In embodiments, a
device may monitor temperature and control its internal
temperature. Temperature control may be useful for quality control.
A device that monitors and controls its temperature may transmit
temperature information to a laboratory; a laboratory may use such
temperature information in the control of the operation of the
instrument, in the oversight of the instrument, and in the analysis
of data transmitted from the instrument. Temperature control may
also be used for regulating the speed of assays performed with the
device. For example, a device may be maintained at a temperature
which optimizes the speed of one or more selected assays (e.g. at
20.degree. C., 22.degree. C., 25.degree. C., 27.degree. C.,
32.degree. C., 35.degree. C., 37.degree. C., 40.degree. C.,
42.degree. C., 45.degree. C., 47.degree. C., 50.degree. C.,
52.degree. C., 55.degree. C., 57.degree. C., 60.degree. C.,
62.degree. C., 65.degree. C., 67.degree. C., 70.degree. C.,
72.degree. C., 75.degree. C., 77.degree. C., 80.degree. C.,
82.degree. C., 85.degree. C., 87.degree. C., 90.degree. C.,
92.degree. C., 95.degree. C., or 97.degree. C.).
In embodiments, a device may be configured to acquire images from
within the device, or within a portion of the device. Such images
may provide information about the position, condition,
availability, or other information regarding components, reagents,
supplies, or samples within the device, and may provide information
used in control of the operation of the device. Such images may be
useful for quality control. A device that acquires images from
within the device may transmit image information to a laboratory; a
laboratory may use such image information in the control of the
operation of the instrument, possibly dynamically or in real-time
continuously or in real-time but in select intervals, in the
oversight of the instrument, and in the analysis of data
transmitted from the instrument.
Device Security
One or more security features may be provided on a sample
processing device. The device may have one or more motion sensor
that may determine when the device changes orientation or is moved.
The device may be able to detect if someone is trying to open the
device. For example one or more sensor may detect if portions of
the device are taken apart. The device may be able to detect if the
device falls or is tipped over. The device may be able to sense any
motion of the device or any motion near the device. For example,
the device may be able to sense if an object or person gets within
a certain distance of the device (e.g., using motion sensors,
optical sensors, thermal sensors, and/or audio sensors). The device
may be able to determine if the device is unplugged or if an error
occurs on the device. Any description of actions that may occur as
a result of device tampering may be applied to any other device
condition as described herein, and vice versa. Accelerometer(s),
vibration sensor(s), and/or tilt sensor(s) are used to determine
rapid movements and jarring of the device. Optionally, cameras on
the outside of the device can image and recognize their
surroundings and/or provide security to the device in terms of
video capture, sounding an alert, or only providing access to
verified individual(s) or device(s).
In some embodiments, an alert may be provided if someone is trying
to open a device, or if someone comes within the device's
proximity. In some instances, an alert may be provided if the
device housing is breached. Similarly, an alert may be provided if
the device falls, tips over, or if an error is detected. The device
may encompass a stabilization system with, optionally, shock
absorbance and dampening capabilities to prevent it from tipping
when for example moving in vehicles at high speeds. In some
instances, if the device detects that the device is being opened,
approached, or tampered with, a camera on the device may capture an
image of the device surroundings. The device may capture an image
of the individual trying to open the device. The data associated
with the device may be sent to the cloud or an external device. The
device associated with the tampering of the device, such as an
image of an individual tampering with the device may be transmitted
from the device. The data associated with the device, which may
include one or more image, may be stored in the device. In the
event that the device is not able to immediately transmit the data,
the data may be transmitted once the device is able and/or
connected to a network.
The device may include one or more microphone or audio detection
device that may be able to record and/or relay sound. For example
if a device is tampered with, the microphone may collect audio
information and the audio information may be stored on the device
or may be transmitted from the device.
Optionally, the device may include one or more location sensing
device. For example, the device may have a GPS tracker within the
device. When any tampering with the device is detected, the
location of the device may be transmitted from the device. The
location may be transmitted to an external device or the cloud. In
some instances, the location of the device may be continuously
broadcast once the tampering is detected, or may be transmitted at
one or more intervals or other detected events. An owner or entity
associated with the device may be able to track the location of the
device. In some instances, a plurality of location sensors may be
provided so that even the device is taken apart and/or one or more
location sensor is found and destroyed, it may be possible to track
other parts of the device. In the event that the device is unable
to transmit the device location at a particular moment, the device
may be able to store the device location and transmit it once it is
able.
In some embodiments, the device may be designed so that it can only
be opened from the inside, or be designed to be only opened from
the inside. For example, in some embodiments the device does not
have fasteners or screws on the outside of the device. Any
mechanical fastening and/or opening features may be on the inside
of the device. The device may be mechanically locked from inside
the housing. The external portion of the housing may include no
exterior fastening/locking mechanisms. The device may be opened
from the inside upon one or more instructions from a controller.
For example, the device may have one or more touchscreen or other
user interface that may accept an instruction from a user for the
device to open. The device may have one or more communication unit
that may receive an instruction from an external device for the
device to open. Based on said instructions, one or more opening
mechanism within the device may cause the device to open. In some
instances, the device may require electrical power for the device
to open. In some instances, the device may only when plugged in.
Alternatively, the device may open when powered by a local energy
storage system or energy generation system. In some instances, the
device may only open if it receives instructions from a user who
has been identified and/or authenticated. For instance, only
certain users may be granted the authority to cause the device to
open.
The device may have one or more local energy storage system. The
energy storage system may permit one or more portions of the device
to operate even if the device is separated from an external energy
source. For example, if the device is unplugged, one or more energy
storage system may permit one or more portion of the device to
operate. In some instances, the energy storage system may permit
all parts of the device to operate. In other examples, the local
energy storage system may permit certain information to be
transmitted from the device to the cloud. The local energy storage
may be sufficient to power a camera that may capture one or more
image of the device surroundings and/or an individual tampering
with the device. The local energy storage may be sufficient to
power a GPS or other location sensor that may indicate the location
of the device. The local energy storage may be sufficient to save
and/or transmit the state of the device e.g., in a log-based
journaling approach so that the device can pick up where it left
off or know what steps need to be performed. The local energy
storage may be sufficient to power a transmission unit that may
send information relating to the device to the cloud and/or an
external device.
In one embodiment, the device and the external controller maintain
a security mechanism by which no unauthorized person with physical
access to the device may be able to retrieve test information and
link it back to an individual, thus protecting the privacy of
patient health data. An example of this would be where the device
captures user identification information, send it to the external
device or cloud, receives a secret key from the cloud and erases
all patient information from the device. In such a scenario, if the
devices send any further data about that patient to the external
device, it will be referred to link through the secret key already
obtained from the external device.
Spectrophotometer
Spectrophotometers may contain a light source and an optical
sensor, and in some embodiments, may be used for measuring any
assay that may be measured by assessing an optical property of the
assay reaction. For example, a spectrophotometer may be used to
measure the color, absorbance, transmittance, fluorescence,
light-scattering properties, or turbidity of a sample. A
spectrophotometer may measure visible light, near-ultraviolet
light, or near-infrared light. A spectrophotometer may be
configured to measure a single wavelength of light, or a range of
wavelengths. In some embodiments, a spectrophotometer may measure a
range of wavelengths between 100-900 nm, such as, for example
200-600 nm, 300-800 nm, 400-800 nm, or 200-800 nm. In some
embodiments, a spectrophotometer may measure an optical property of
a single sample at multiple different wavelengths (e.g. the
absorbance of a sample at multiple wavelengths). A
spectrophotometer may be configured such that it may direct light
of one or more different wavelengths to a sample and it may detect
the transmittance, reflection, or emission of one or more different
wavelengths of light by the sample. A spectrophotometer may direct
light of different wavelengths to a sample by, for example, by
containing contain a monochromator and adjustable filter, such that
light from the light source may be filtered so that only a selected
wavelength or range of wavelengths reaches the sample. In some
embodiments, transmitted light is separated spectrally using a
grating, and the spectrally separated signal is read by a spatial
sensor. In some embodiments, the light source could be a
broad-spectrum light source such as a Xe, Hg--Xe, Hg--Ar light
source. The light source can either be pulsed or continuous, and
may allow for adjustable intensity. In another example, a
spectrophotometer may contain at least two different light sources
which emit light of different peak wavelength ranges (e.g.
different LEDs). A spectrophotometer may also be configured such
that the optical sensor only detects light of a certain wavelength
or range of wavelengths (e.g. by use of a filter in front of the
sensor). A spectrophotometer may be a dedicated spectrophotometer
(i.e. it may be optimized for performing spectrophotometric
readings; for example, it may not contain extraneous hardware, such
as a sample heater). Optionally, the spectrophotometer may, in
certain embodiments, include an electrode or electrochemical
detection unit that can be used in conjunction with optical
measurements being performed. Optionally, other hardware such as
heating units, cuvette holders, or the like are not excluded in
other embodiments of the spectrophotometer.
FIGS. 31A-31D show a spectrophotometer 7400, in accordance with an
embodiment of the invention. The spectrophotometer 7400 may be the
spectrophotometer 714 described in the context of FIG. 7. The
spectrophotometer 7400 includes a detection block 7401 ("block")
having a laser diode, light filter, a sensor (for detecting
electromagnetic radiation) and a printed circuit board. In some
cases, the spectrophotometer 7400 includes a controller having one
or more processors. A light source, such as but not limited to a
xenon light source, is located in a compartment 7402 adjacent the
block 7401. The block 7401 includes a sample receptacle (or inlet)
port or channel 7403, which is configured to accept a first
consumable 7404 or a second consumable 7405. The first consumable
7404 is a cuvette and the second consumable is a tip. The
consumables 7404 and 7405 are configured to be moved, carried and
manipulated by various sample handling systems (e.g., robots)
provided herein. The cuvette includes sample holders. Some
embodiments may use a light source with specific wavelengths.
Optionally, other embodiments do not specifically limit the
wavelengths.
With reference to FIG. 31C, the first consumable 7404 is configured
to be mounted in the port 7403. Individual sample holders 7406 of
the first consumable 7404 are configured to be placed in the line
of sight of the light source 7407 (e.g., xenon light source),
either in direct line of sight or with the aid of optics. Light
from the individual sample holders passes to a detector 7408 (e.g.,
CCD sensor) for detection. With reference to FIG. 31D, the second
consumable 7405 is inserted into the port 7403 for sample
detection. Light from a laser diode 7409 is directed to the second
consumable 7405. Light then passes to a filter 7410, which is moved
into the path of light emanating from the second consumable 7405.
Light is then directed to the sensor 7408. Light from the first
consumable 7404 or second consumable 7405 may be directed to the
sensor 7408 using optics.
The consumables 7404 and 7405 are configured to hold a sample for
detection. The consumables 7404 and 7405 may be discarded after
use. The spectrophotometer 7400 in some cases is configured to hold
one consumable at a time, though in some situations the
spectrophotometer 7400 may hold multiple consumables during
processing. In some situations, non-consumable sample holders may
be used.
In one embodiment, the fluid handling device might be used to
transfer an assay vessel into the spectrophotometer where an
optical characteristic of the sample is measured. This
characteristic may include, but not limited to absorbance,
fluorescence, turbidity, etc. The spectrophotometer might include
one or more sensors, capable of handling one or more sample
simultaneously. Analogously, one or more signals (absorbance,
turbidity, etc.) might be measured simultaneously.
The spectrometer may include a PCB board that connects to an
external computer and/or processing unit. Alternatively, the
computer may be part of the PCB board itself. The computer may
receive data from the spectrophotometer sensor, after being
processed by the board. The computer may be programmed to analyze
the data sent from the board in real-time. In one embodiment, the
results of the computer analysis may provide feedback to the board.
The feedback may include changes in acquisition time, number of
acquisitions for averaging, etc. In some embodiments, this feedback
might be used to auto-calibrate the spectrophotometer
components.
In some embodiments, the light source and optical sensor of a
spectrometer may be oriented in-line with each other. In other
embodiments, the optical sensor is at an angle to the light path
from the light source (for example, 45 or 90 degrees). An optical
sensor at an angle from the light path from the light source may be
used, for example, for detecting light scattered by a sample or
light emitted by a fluorescent compound.
Referring now to FIG. 31E, yet another embodiment of a
spectrophotometer will now be described. This embodiment shown in
FIG. 31E uses a different mechanism 7440 for the transport of the
cuvette from the cartridge. Instead of using a pipette or other
instrument to lift the cuvette out of the pipette and into the
detector station, this embodiment uses a gear in the mechanism 7440
to engage gear teeth 7442 formed in the cuvette. This allows for
the cuvette 7444 to be moved out from the cartridge without having
to use a lifting mechanism such as the pipette, a robot, or other
end-effector in the system, which then frees that hardware to
perform other tasks. As seen in FIG. 31E, the cuvette may be moved
to detector 7446 which may be single detector or an arrayed
detector.
Referring now to FIGS. 31F and 31G, a still further embodiment of a
spectrophotometer will now be described. FIG. 31F is a top-down
view of a fiber-based spectrophotometer wherein the illumination
source and/or the detector can be spaced apart from the sample
location and are connected by fiberoptics 7460 and 7462. This may
allow for greater flexibility in placement of components.
Optionally, this also allows for specific illumination conditions
for each sample well of the cuvette, multiple illumination
wavelengths per sample well 7464, or other custom illumination or
detection based on the ability to provide and receive wavelengths
of light from and to certain illumination sources and detectors. By
way of non-limiting example, the detector may be a single detector
as shown in this figure or it may be an arrayed detector.
FIG. 31G shows a cutaway perspective view showing the inbound light
pathway 7470 and the outbound light pathway 7472. This embodiment
showing a fiber coupling 7474, a collimator 7476, a mirror 7478, a
filter 7480, a reflector 7482, and a fiber coupling 7484 for the
outbound light pathway to the detector. In one embodiment, the
sample well 7464 may be part of a cuvette, or optionally, it may be
an opening designed to hold a reaction vessel. A fiber-based
version of the spectrophotometer can separate the illumination
source and the detector from the sample handling unit. The fibers
could carry the light source from a separate location, creating a
shared illumination source. This provides for greater flexibility
in terms of light source placement and sharing.
Optionally, there may be a cuvette that is configured to be
disconnected at the detector and having features such as but not
limited to ledges, ridges, lips, hands, or other features to
stabilize the cuvette while it is in the detector. The
spectrophotometer may have a receiving area that is shaped to
accept this type of cuvette. The system may also be configured to
accept a single cuvette or have a cuvette that can be loaded with
other sample vessels in a sequential, non-simultaneous manner to
provide greater flexibility in scheduling.
Fiberoptics can also provide for multiple channel configurations to
enable greater range of excitation and detector configurations. The
fiberoptics can also allow for multiple internal reflections in the
cuvette designed to cause this multiple internal reflection path to
extend the pathlength beyond the physical geometric pathlength of
the cuvette. Some embodiment may have side walls of the cuvette
that have inner wall surfaces with a convex shape such that the
vessel that causes reflections of light entering therein.
FIG. 52 shows a schematic diagram of the workflow of one embodiment
of the system. Steps illustrated by boxes numbered from 1 to 4
represent pre-analytic steps. Pre-analytic steps include sample
collection, sample processing, reagent addition, signal generation,
and transmission. Steps illustrated by boxes numbered from 5 to 8
represent analytic steps. Analytic steps include analysis of data
received from a device at a sample collection site, oversight,
including analysis of controls, calibrations, replicates, outliers,
device and sample identification and quality information, and
generation of the reportable. Transmission of the report to the
health care professional represents a post-analytic step.
Post-analytic steps include further review of the analysis of data,
and review of report generation and of the report generated for a
particular test prior to sign off by CLIA or other regulatory
laboratory personnel and transmission to the physician who ordered
a given test.
The publications discussed or cited herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed. All publications mentioned
herein are incorporated herein by reference to disclose and
describe the structures and/or methods in connection with which the
publications are cited. The following applications are also
incorporated herein by reference for all purposes: U.S. Pat. Nos.
7,888,125, 8,007,999, 8,088,593 and U.S. Publication No.
US20120309636, PCT Application No. PCT US2012/057155, U.S. patent
application Ser. No. 13/244,952, and PCT Application No.
PCT/US2011/53188, filed Sep. 25, 2011. PCT Application No.
PCT/US2011/53188, filed Sep. 25, 2011, U.S. patent application Ser.
No. 13/244,946, filed Sep. 26, 2011, PCT Application No.
PCT/US11/53189, filed Sep. 25, 2011, Patent Cooperation Treaty
Application No. PCT/US2011/53188; Patent Cooperation Treaty
Application No. PCT/US2012/57155; Patent Cooperation Treaty
Application No. PCT/US14/16997; U.S. Patent Application 61/944,567,
U.S. patent application Ser. No. 13/244,947; U.S. patent
application Ser. No. 13/244,949; U.S. patent application Ser. No.
13/244,950; U.S. patent application Ser. No. 13/244,951; U.S.
patent application Ser. No. 13/244,952; U.S. patent application
Ser. No. 13/244,953; U.S. patent application Ser. No. 13/244,954;
U.S. patent application Ser. No. 13/244,956, all of which
applications are hereby incorporated by reference in their
entireties.
While preferred embodiments of the present invention have been
shown and described herein, it will be obvious to those skilled in
the art that such embodiments are provided by way of example only.
Numerous variations, changes, and substitutions will now occur to
those skilled in the art without departing from the invention. It
should be understood that various alternatives to the embodiments
of the invention described herein may be employed in practicing the
invention. Any feature, whether preferred or not, may be combined
with any other feature, whether preferred or not. The appended
claims are not to be interpreted as including means-plus-function
limitations, unless such a limitation is explicitly recited in a
given claim using the phrase "means for." It should be understood
that as used in the description herein and throughout the claims
that follow, the meaning of "a," "an," and "the" includes plural
reference unless the context clearly dictates otherwise. For
example, a reference to "an assay" may refer to a single assay or
multiple assays. Also, as used in the description herein and
throughout the claims that follow, the meaning of "in" includes
"in" and "on" unless the context clearly dictates otherwise.
Finally, as used in the description herein and throughout the
claims that follow, the meaning of "or" includes both the
conjunctive and disjunctive unless the context expressly dictates
otherwise. Thus, the term "or" includes "and/or" unless the context
expressly dictates otherwise.
Intentionally Left Blank
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